rs202039659

chr12-120999307-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_000545.8(HNF1A):c.1541A>G(p.His514Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,613,828 control chromosomes in the GnomAD database, including 1 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 3.44

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000545.8
• BP4: Computational evidence support a benign effect (MetaRNN=0.039476186).
• BP6: Variant 12-120999307-A-G is Benign according to our data. Variant chr12-120999307-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435421.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Benign=1, Likely_benign=1}. Variant chr12-120999307-A-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.1541A>G	p.His514Arg	missense_variant	8/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.1541A>G	p.His514Arg	missense_variant	8/10
HNF1A	NM_001406915.1	c.1349A>G	p.His450Arg	missense_variant	7/9
HNF1A	XM_024449168.2	c.1541A>G	p.His514Arg	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.1541A>G	p.His514Arg	missense_variant	8/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151994 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000430 AC: 108 AN: 251200 Hom.: 0 AF XY: 0.000420 AC XY: 57 AN XY: 135872

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 SAS 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.: 1 Cov.: 32 AF XY: 0.000226 AC XY: 164 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00830

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000692

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000270 AC: 41 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000480 Hom.: 0

Bravo AF: 0.000317

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 22, 2023	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	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:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	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) -

Maturity-onset diabetes of the young type 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 24, 2017

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

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2018

The p.H514R variant (also known as c.1541A>G), located in coding exon 8 of the HNF1A gene, results from an A to G substitution at nucleotide position 1541. The histidine at codon 514 is replaced by arginine, an amino acid with highly similar properties. This variant was first reported in a 29-year-old female and her mother, who were both diagnosed with type 2 diabetes (Gragnoli C et al. Diabetologia, 2001 Oct;44:1326-9). In another study, this variant was identified in a sample submitted for maturity-onset diabetes of the young genetic testing; however, specific clinical information was not provided and this variant was reported as a variant of uncertain significance (Bennett JT et al. Mol. Genet. Metab., 2015 Mar;114:451-8). This variant was also identified in a cohort of individuals with diabetes as well as in an 18-year-old female with negative autoantibodies and no family history of diabetes (Flannick J et al. Nat. Genet., 2013 Nov;45:1380-5; Karaca E et al. Diabetes Metab Syndr, 2017 Nov;11 Suppl 1:S491-S496). Functional analyses in HeLa cells demonstrated a reduction of transcriptional activity and nuclear localization compared to wild type, but at higher levels than known mutations in the HNF1A gene (Najmi LA et al. Diabetes, 2017 02;66:335-346). Based on data from gnomAD, the G allele has an overall frequency of approximately 0.039% (109/276936) total alleles studied. The highest observed frequency was 0.807% (82/10150) of Ashkenazi Jewish alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

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

Oct 26, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.039	T;T;T;T;T
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	0.57	N;N;N;N
PrimateAI	Uncertain	0.70	T
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	T
GERP RS		4.3
gMVP		0.71

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

Other links and lift over

dbSNP: rs202039659; hg19: chr12-121437110; COSMIC: COSV105084529; COSMIC: COSV105084529;