chr12-120999307-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. BA1BP5PP3

This summary comes from the ClinGen Evidence Repository: The c.1541A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to arginine at codon 514 (p.(His514Arg)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.85, which is greater than the MDEP VCEP threshold of 0.70 (PP3). However, this variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001150, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). Additionally, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1541A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 08/11/2023): BA1, BP5, PP3. While this variant is benign for HNF1A-monogenic diabetes, there is evidence to suggest that this variant may act as a risk allele for type 2 diabetes (PMID:11692182, 27899486, 36216889, 33046911). LINK:https://erepo.genome.network/evrepo/ui/classification/CA6832103/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:8B:4

Conservation

PhyloP100: 3.44

Publications

14 publications found

Variant links:

COSMIC-nc: COSV105084529

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 -8 ACMG points.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.1541A>G	p.His514Arg	missense_variant	Exon 8 of 10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.1541A>G	p.His514Arg	missense_variant	Exon 8 of 10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.1349A>G	p.His450Arg	missense_variant	Exon 7 of 9		NP_001393844.1
HNF1A	XM_024449168.2 link	c.1541A>G	p.His514Arg	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.1541A>G	p.His514Arg	missense_variant	Exon 8 of 10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000430

AC:

108

AN:

251200

AF XY:

0.000420

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00814

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000233

AC:

340

AN:

1461718

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

164

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00830

AC:

217

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53266

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000692

AC:

AN:

1111994

Other (OTH)

AF:

0.000580

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000270

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41480

American (AMR)

AF:

0.000327

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00750

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67990

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000528

Hom.:

Bravo

AF:

0.000317

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Uncertain:8Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Dec 22, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HNF1A c.1541A>G (p.His514Arg) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 1613828 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 9 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 benign. c.1541A>G has been reported in the literature in individuals affected with diabetes and individuals from MODY cohort studies without strong evidence of segregation (examples: Behn_1998, Gragnoli_2001,Flannick_2013, Karaca_2017, Yu_2019, Elashi_2022). 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 that this variant had a reduction in transcriptional activity and abnormal nuclear localization compared to Wild-Type (Najmi_2017). The following publications have been ascertained in the context of this evaluation (PMID: 9604876, 36613572, 24097065, 11692182, 28395978, 27899486, 10333057, 31264968). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as VUS (n=8) and Benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Jan 17, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

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.His514Arg variant in HNF1A is classified as likely benign because it has been identified in 0.8% (83/10366) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. ACMG/AMP Criteria applied: BS1. -

not provided

Uncertain:2Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 21, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32910913, 31264968, 28395978, 27899486, 24097065, 11692182) -

Jun 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Maturity-onset diabetes of the young type 3

Uncertain:2

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Monogenic diabetes

Uncertain:1Benign:1

Mar 24, 2017

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria:PP3 (8 predictors), BP4 (2 predictors), PS3 (PMID: 27899486 shows decreased activity and altered localization) -

Feb 20, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.1541A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to arginine at codon 514 (p.(His514Arg)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.85, which is greater than the MDEP VCEP threshold of 0.70 (PP3). However, this variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001150, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). Additionally, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1541A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 08/11/2023): BA1, BP5, PP3. While this variant is benign for HNF1A-monogenic diabetes, there is evidence to suggest that this variant may act as a risk allele for type 2 diabetes (PMID: 11692182, 27899486, 36216889, 33046911). -

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

Oct 26, 2022

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1541A>G variant identified in the HNF1A gene has been previously reported in individuals with diabetes in the literature [PMID:31264968, 28395978, 27899486, others], however it has also been reported in individuals without family history of diabetes [PMID: 31264968]. This variant has been reported in ClinVar as both a Variant of Uncertain Significance and as Likely Benign (VarID:435421). The c.1541A>G variant is observed in population databases (gnomADv2.1, gnomADv3.1.2, BRAVO-TOPMed) with highest allele frequency of 3.96e-4-4 (112 heterozygotes, 0 homozygotes, gnomADv2.1). The c.1541A>G variant is located within exon 8 of this 10-exon gene and is predicted to substitute a evolutionarily well conserved Histidine for Arginine at amino acid 514/632 (p.(His514Arg)),outside of predicted domains of HNF1A (UniProtKB:P20823). In silico algorithms predict this variant to have a damaging effect to protein function (REVEL=0.85) and this is supported by in vitro functional studies suggest that the p.His514Arg variant results in a functionally impaired protein with ~50-60% activity, and that this variant may lead to aggregation of HNF1A within the cell [PMID: 27899486]. Additional studies are needed to confirm this in vitro finding and clinical correlation with moderately reduced functional impairment is needed. Based on the available evidence, the c.1541A>G p.(His514Arg) variant identified in the HNF1A gene is reported as a Variant of Uncertain Significance. -

Maturity onset diabetes mellitus in young

Benign:1

May 08, 2025

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

0.15

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

.;D;.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.039

T;T;T;T;T

MetaSVM

Pathogenic

0.93

PhyloP100

3.4

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.9

D;.;.;D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.016

D;.;.;D;D

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

1.0

.;.;.;.;D

Vest4

0.62

MVP

0.97

MPC

0.21

ClinPred

0.26

GERP RS

4.3

gMVP

0.71

Mutation Taster

=7/93

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

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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