rs137853239

chr12-120999606-C-Gchr12-120999606-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS1_ModeratePP3_Moderate

The NM_000545.8(HNF1A):c.1747C>G(p.Arg583Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R583Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2O:1

Conservation

PhyloP100: -0.266

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 Uncertain_significance. Variant got 4 ACMG points.

PS1

Transcript NM_000545.8 (HNF1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PP3

MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HNF1A	NM_000545.8 linkuse as main transcript	c.1747C>G	p.Arg583Gly	missense_variant	9/10	ENST00000257555.11
HNF1A	NM_001306179.2 linkuse as main transcript	c.1768C>G	p.Arg590Gly	missense_variant	9/10
HNF1A	NM_001406915.1 linkuse as main transcript	c.1555C>G	p.Arg519Gly	missense_variant	8/9
HNF1A	XM_024449168.2 linkuse as main transcript	c.1840C>G	p.Arg614Gly	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.1747C>G	p.Arg583Gly	missense_variant	9/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000416

AC:

AN:

240184

Hom.:

AF XY:

0.00000763

AC XY:

AN XY:

131116

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000552

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1458946

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725802

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 3

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided, no classification provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2015	- -

Type 1 diabetes mellitus 20

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1997

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2022

This variant is present in population databases (rs137853239, gnomAD 0.006%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 14932). This missense change has been observed in individuals with diabetes (PMID: 9313763, 11942313, 12355088, 21236713). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 583 of the HNF1A protein (p.Arg583Gly). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.28

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Uncertain

-0.094

MutationTaster

Benign

0.027

A;A;A;A

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.7

N;.;.;N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.0060

D;.;.;D;D

Sift4G

Benign

0.43

T;T;T;T;T

Polyphen

0.15

.;.;.;.;B

Vest4

0.57

MutPred

0.73

.;.;.;.;Gain of glycosylation at S592 (P = 0.0685);

MVP

1.0

MPC

0.36

ClinPred

0.31

GERP RS

0.35

gMVP

0.79

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