rs137853242

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000545.8(HNF1A):c.1748G>A(p.Arg583Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000856 in 1,611,350 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R583G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 2 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5B:5

Conservation

PhyloP100: 2.07

Publications

21 publications found

Variant links:

Genes affected

HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

HNF1A Gene-Disease associations (from GenCC):

monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
type 1 diabetes mellitus 20
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
maturity-onset diabetes of the young type 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
hyperinsulinism due to HNF1A deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
nonpapillary renal cell carcinoma
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

HNF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013279617).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000584 (89/152300) while in subpopulation AMR AF = 0.000915 (14/15298). AF 95% confidence interval is 0.000612. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 89 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 9 of 10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.1769G>A	p.Arg590Gln	missense_variant	Exon 9 of 10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.1556G>A	p.Arg519Gln	missense_variant	Exon 8 of 9		NP_001393844.1
HNF1A	XM_024449168.2 link	c.1841G>A	p.Arg614Gln	missense_variant	Exon 8 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.1748G>A	p.Arg583Gln	missense_variant	Exon 9 of 10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000478

AC:

115

AN:

240352

AF XY:

0.000457

show subpopulations

Gnomad AFR exome

AF:

0.0000658

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000552

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000941

Gnomad OTH exome

AF:

0.000338

GnomAD4 exome

AF:

0.000885

AC:

1291

AN:

1459050

Hom.:

Cov.:

AF XY:

0.000851

AC XY:

618

AN XY:

725858

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33452

American (AMR)

AF:

0.000336

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.0000385

AC:

AN:

51886

Middle Eastern (MID)

AF:

0.000188

AC:

AN:

5316

European-Non Finnish (NFE)

AF:

0.00111

AC:

1233

AN:

1111522

Other (OTH)

AF:

0.000531

AC:

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

130

195

260

325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000584

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41562

American (AMR)

AF:

0.000915

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000779

AC:

AN:

68022

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000626

Hom.:

Bravo

AF:

0.000669

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000699

AC:

ExAC

AF:

0.000495

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HNF1A c.1748G>A; p.Arg583Gln variant (rs137853242) is reported in families with MODY (Bellanne-Chantelot 2008, Ellard 2006), but is also reported in individuals unaffected with diabetes from the Framingham Heart Study (Flannick 2013). Functional studies showed only a mild effect on transcriptional activity and nuclear localization, suggesting this variant may be benign (Najmi 2017). This variant is reported with conflicting interpretations of pathogenicity in ClinVar (Variation ID: 14940). It is observed in the general population with an overall allele frequency of 0.05% (125/271728 alleles) in the Genome Aggregation Database. The arginine at codon 583 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.552). Due to conflicting evidence, the clinical significance of this variant is uncertain at this time. References: Bellanne-Chantelot C et al. The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes. 2008 Feb;57(2):503-8. PMID: 18003757. Ellard S et al. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young. Hum Mutat. 2006 Sep;27(9):854-69. PMID: 16917892. Flannick J et al. Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Nat Genet. 2013 Nov;45(11):1380-5. PMID: 24097065. Najmi LA et al. Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population. Diabetes. 2017 Feb;66(2):335-346. PMID: 27899486. -

Dec 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Apr 17, 2024

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 06, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg583Gln variant in HNF1A is classified as likely benign because it has been identified in 0.09% (107/121650) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In addition, computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. This variant has been reported in ClinVar (Variation ID: 14940). ACMG/AMP Criteria applied: BS1_Supporting, BP4. -

Sep 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HNF1A c.1748G>A (p.Arg583Gln) results in a conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006817) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 240352 control chromosomes, predominantly at a frequency of 0.00094 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 40 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05). c.1748G>A has been reported in the literature in individuals affected with adult onset NIDDM and did not segregate with disease in one family with early onset diabetes (example, Bluteau_2002, Owen_2003, Urhammer_1997, Najmi_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal transcriptional activity and nuclear localization. The following publications have been ascertained in the context of this evaluation (PMID: 11942313, 9313764, 10333057, 12832318, 12355088, 16917892, 12359128, 9112026, 20393147, 24097065, 27899486). ClinVar contains an entry for this variant (Variation ID: 14940). Based on the evidence outlined above, the variant was classified as likely benign. -

Maturity-onset diabetes of the young type 3

Pathogenic:2

Oct 01, 2002

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

- -

May 13, 2022

National Newborn Screening Laboratory, Hospital Nacional de Niños

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

85% of missense variants in HNF1A are pathogenic Also, 7 pathogenic predictions vs 4 bening predictions It was observed in patients with hyperglycemia . Reported in literature with reduced transcripcional activity -

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C2675866:Type 1 diabetes mellitus 20

Uncertain:1

Dec 29, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The heterozygous missense variant c.1748G>A (p.Arg583Gln) identified in the HNF1A gene has been reported in two subjects (out of 245 patients) with adult-onset non-insulin-dependent diabetes mellitus (PMID: 9112026), in a single-family with early-onset diabetes [variant detected in two affected individuals but was not present in one diabetic family-member; PMID:12832318], and a Japanese patient with type 1 diabetes (PMID: 9313763). The variant has been reported as a Variant of Uncertain Significance in a cohort of 110 patients with maturity-onset diabetes of the young [PMID:32041611]. However, the number of affected individuals with the heterozygous c.1748G>A (p.Arg583Gln) HNF1A variant was not specified [PMID:32041611]. The variant has also been reported in four individuals (out of1,435) without diabetes from a Framingham Heart Study cohort (PMID: 27899486). The variant has 0.0004600 allele frequency (125 heterozygous alleles and no homozygous allele) in the gnomAD database (v2.1.1 and v3.1.2). The variant is reported as a Variant of Uncertain Significance and Likely Benign in the ClinVar database (Variation ID: 14940). The variant affects a moderately conserved residue (Arg583) located in the transactivation domain of the HNF1A protein (PMID:27899486) and is predicted deleterious by multiple in silico prediction tools (CADD score = 23.9, REVEL score = 0.552). In vitro functional analysis suggest that the c.1748G>A (p.Arg583Gln) variant is associated with reduced transcriptional activity and nuclear localization (PMID: 27899486). Based on the available evidence, the heterozygous c.1748G>A (p.Arg583Gln) variant identified in the HNF1A gene is reported as a Variant of Uncertain Significance. -

HNF1A-related disorder

Uncertain:1

Feb 08, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The HNF1A c.1748G>A variant is predicted to result in the amino acid substitution p.Arg583Gln. This variant has been reported in patients with maturity-onset diabetes of the young (MODY), but the pathogenicity is unknown (Ziemssen et al. 2002. PubMed ID: 11942313; Flannick et al. 2013. PubMed ID: 24097065; Najmi et al. 2017. PubMed ID: 27899486). In the Najmi et al. study, functional evaluation showed that this variant resulted in 63% of transcriptional activity while as control well-established pathogenic variants only produced up to 14-18% of transcriptional activity, indicating this variant is unlikely pathogenic. This variant is reported in 0.088% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely to common to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Maturity onset diabetes mellitus in young

Benign:1

Oct 27, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

.;D;.;T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.013

T;T;T;T;T

MetaSVM

Uncertain

0.13

PhyloP100

2.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.89

N;.;.;N;N

REVEL

Uncertain

0.55

Sift

Uncertain

0.010

D;.;.;D;D

Sift4G

Benign

0.56

T;T;T;T;T

Polyphen

0.0050

.;.;.;.;B

Vest4

0.33

MVP

1.0

MPC

0.33

ClinPred

0.022

GERP RS

3.9

gMVP

0.74

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over