rs2464196

Variant names:

• chr12-120997624-G-A
• rs2464196
• NM_000545.8:c.1460G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-120997624-G-A
• chr12-120997624-G-C
• chr12-120997624-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S487G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.27 (6416 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74045 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 1.05
• Publications: 159 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1460G>A	p.Ser487Asn	missense_variant	Exon 7 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1460G>A	p.Ser487Asn	missense_variant	Exon 7 of 10		NP_001293108.2
HNF1A	XM_024449168.2	c.1460G>A	p.Ser487Asn	missense_variant	Exon 7 of 9		XP_024304936.1
HNF1A	NM_001406915.1	c.1309+882G>A		intron_variant	Intron 6 of 8		NP_001393844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1460G>A	p.Ser487Asn	missense_variant	Exon 7 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41508 AN: 152026 Hom.: 6414 Cov.: 32

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

GnomAD2 exomes AF: 0.337 AC: 83546 AN: 247590 AF XY: 0.343

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 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.: 42 AF XY: 0.316 AC XY: 229707 AN XY: 726350

African (AFR) AF: 0.121 AC: 4034 AN: 33468

American (AMR) AF: 0.373 AC: 16586 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 12235 AN: 26106

East Asian (EAS) AF: 0.523 AC: 20716 AN: 39606

South Asian (SAS) AF: 0.411 AC: 35356 AN: 86098

European-Finnish (FIN) AF: 0.309 AC: 16395 AN: 53086

Middle Eastern (MID) AF: 0.484 AC: 2789 AN: 5766

European-Non Finnish (NFE) AF: 0.295 AC: 328233 AN: 1111166

Other (OTH) AF: 0.326 AC: 19677 AN: 60350

GnomAD4 genome AF: 0.273 AC: 41510 AN: 152144 Hom.: 6416 Cov.: 32 AF XY: 0.280 AC XY: 20838 AN XY: 74374

African (AFR) AF: 0.128 AC: 5314 AN: 41534

American (AMR) AF: 0.345 AC: 5265 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1594 AN: 3470

East Asian (EAS) AF: 0.486 AC: 2516 AN: 5172

South Asian (SAS) AF: 0.403 AC: 1945 AN: 4822

European-Finnish (FIN) AF: 0.321 AC: 3402 AN: 10584

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.299 AC: 20345 AN: 67974

Other (OTH) AF: 0.312 AC: 657 AN: 2108

Alfa AF: 0.302 Hom.: 26154

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:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6 Other:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 21, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Nov 18, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Maturity-onset diabetes of the young type 3 Benign:3

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Type 2 diabetes mellitus Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Benign:1

Sep 27, 2015

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	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
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	D
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	T
PhyloP100		1.1
PrimateAI	Uncertain	0.54	T
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	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.75
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2464196; hg19: chr12-121435427; COSMIC: COSV57459963; COSMIC: COSV57459963;