rs137853242

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5BP4_StrongBS2

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. 11/19 in silico tools predict 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 Likely pathogenic.

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:4

Conservation

PhyloP100: 2.07

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

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

BS2

High AC in GnomAd4 at 89 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HNF1A	NM_000545.8 linkuse as main transcript	c.1748G>A	p.Arg583Gln	missense_variant	9/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 linkuse as main transcript	c.1769G>A	p.Arg590Gln	missense_variant	9/10		NP_001293108.2
HNF1A	NM_001406915.1 linkuse as main transcript	c.1556G>A	p.Arg519Gln	missense_variant	8/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.1841G>A	p.Arg614Gln	missense_variant	8/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.1748G>A	p.Arg583Gln	missense_variant	9/10	1	NM_000545.8	ENSP00000257555	P4

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

GnomAD3 exomes

AF:

0.000478

AC:

115

AN:

240352

Hom.:

AF XY:

0.000457

AC XY:

AN XY:

131218

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 SAS exome

AF:

0.0000658

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

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000385

Gnomad4 NFE exome

AF:

0.00111

Gnomad4 OTH exome

AF:

0.000531

GnomAD4 genome

AF:

0.000584

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000779

Gnomad4 OTH

AF:

0.000946

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:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -

Maturity-onset diabetes of the young type 3

Pathogenic:2

Pathogenic, flagged submission	literature only	OMIM	Oct 01, 2002	- -
Likely pathogenic, flagged submission	research	National Newborn Screening Laboratory, Hospital Nacional de Niños	May 13, 2022	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 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 18, 2020	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. Three 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 38 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1748G>A has been reported in the literature in individuals affected with adult onset NIDDM and did not co-segregate with disease in one family early onset diabetes (example, Bluteau_2002, Owen_2003, Urhammer_1997, Najmi_2017). These data do not allow any conclusion about variant significance. 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. At-least one submitter cites overlapping evidence utilized in the context of this evaluation and reports the variant as not having undergone a full assessment. Based on the evidence outlined above, the variant was classified as likely benign. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Dec 29, 2021

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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2016

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

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

MutationTaster

Benign

0.98

N;N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over