rs2464196

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000545.8(HNF1A):c.1460G>A(p.Ser487Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,612,298 control chromosomes in the GnomAD database, including 80,461 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.27 ( 6416 hom., cov: 32)

Exomes 𝑓: 0.31 ( 74045 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 1.05

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001606971).

BP6

Variant 12-120997624-G-A is Benign according to our data. Variant chr12-120997624-G-A is described in ClinVar as [Benign]. Clinvar id is 129230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120997624-G-A is described in Lovd as [Benign]. Variant chr12-120997624-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.1460G>A	p.Ser487Asn	missense_variant	7/10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.1460G>A	p.Ser487Asn	missense_variant	7/10		NP_001293108.2	P20823E0YMI7
HNF1A	XM_024449168.2 link	c.1460G>A	p.Ser487Asn	missense_variant	7/9		XP_024304936.1
HNF1A	NM_001406915.1 link	c.1309+882G>A		intron_variant			NP_001393844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.1460G>A	p.Ser487Asn	missense_variant	7/10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.273

AC:

41508

AN:

152026

Hom.:

6414

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.357

Gnomad AMR

AF:

0.345

Gnomad ASJ

AF:

0.459

Gnomad EAS

AF:

0.487

Gnomad SAS

AF:

0.404

Gnomad FIN

AF:

0.321

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.299

Gnomad OTH

AF:

0.305

GnomAD3 exomes

AF:

0.337

AC:

83546

AN:

247590

Hom.:

14870

AF XY:

0.343

AC XY:

45944

AN XY:

134104

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.371

Gnomad ASJ exome

AF:

0.462

Gnomad EAS exome

AF:

0.486

Gnomad SAS exome

AF:

0.417

Gnomad FIN exome

AF:

0.312

Gnomad NFE exome

AF:

0.306

Gnomad OTH exome

AF:

0.338

GnomAD4 exome

AF:

0.312

AC:

456021

AN:

1460154

Hom.:

74045

Cov.:

AF XY:

0.316

AC XY:

229707

AN XY:

726350

show subpopulations

Gnomad4 AFR exome

AF:

0.121

Gnomad4 AMR exome

AF:

0.373

Gnomad4 ASJ exome

AF:

0.469

Gnomad4 EAS exome

AF:

0.523

Gnomad4 SAS exome

AF:

0.411

Gnomad4 FIN exome

AF:

0.309

Gnomad4 NFE exome

AF:

0.295

Gnomad4 OTH exome

AF:

0.326

GnomAD4 genome

AF:

0.273

AC:

41510

AN:

152144

Hom.:

6416

Cov.:

AF XY:

0.280

AC XY:

20838

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.128

Gnomad4 AMR

AF:

0.345

Gnomad4 ASJ

AF:

0.459

Gnomad4 EAS

AF:

0.486

Gnomad4 SAS

AF:

0.403

Gnomad4 FIN

AF:

0.321

Gnomad4 NFE

AF:

0.299

Gnomad4 OTH

AF:

0.312

Alfa

AF:

0.311

Hom.:

19018

Bravo

AF:

0.267

TwinsUK

AF:

0.294

AC:

1090

ALSPAC

AF:

0.300

AC:

1156

ESP6500AA

AF:

0.123

AC:

541

ESP6500EA

AF:

0.311

AC:

2676

ExAC

AF:

0.331

AC:

40202

Asia WGS

AF:

0.419

AC:

1452

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Maturity-onset diabetes of the young type 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Type 2 diabetes mellitus

Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

rs2464196 of HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria and may respond to sulfonylureas. -

Nonpapillary renal cell carcinoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Maturity onset diabetes mellitus in young

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2015

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

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

.;T;T;.;T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.52

T;T;T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.61

N;.;.;.;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.11

T;.;.;.;T;T

Sift4G

Benign

0.27

T;T;T;T;T;T

Polyphen

0.0

.;.;.;.;.;B

Vest4

0.13

MPC

0.12

ClinPred

0.0043

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.75

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