rs1169288

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The XM_024449168.2(HNF1A):c.79A>C(p.Ile27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,612,800 control chromosomes in the GnomAD database, including 91,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.29 ( 7186 hom., cov: 32)

Exomes 𝑓: 0.33 ( 83862 hom. )

Consequence

HNF1A
XM_024449168.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:15O:3

Conservation

PhyloP100: 3.21

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:

HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

HNF1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011825562).

BP6

Variant 12-120978847-A-C is Benign according to our data. Variant chr12-120978847-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14937.We mark this variant Likely_benign, oryginal submissions are: {Likely_pathogenic=1, Benign=14, not_provided=1}. Variant chr12-120978847-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.79A>C	p.Ile27Leu	missense_variant	Exon 1 of 10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.79A>C	p.Ile27Leu	missense_variant	Exon 1 of 10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.79A>C	p.Ile27Leu	missense_variant	Exon 1 of 9		NP_001393844.1
HNF1A	XM_024449168.2 link	c.79A>C	p.Ile27Leu	missense_variant	Exon 1 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.79A>C	p.Ile27Leu	missense_variant	Exon 1 of 10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.289

AC:

43843

AN:

151834

Hom.:

7184

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.400

Gnomad AMR

AF:

0.344

Gnomad ASJ

AF:

0.458

Gnomad EAS

AF:

0.411

Gnomad SAS

AF:

0.417

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.328

Gnomad OTH

AF:

0.311

GnomAD3 exomes

AF:

0.355

AC:

88280

AN:

248756

Hom.:

16580

AF XY:

0.361

AC XY:

48797

AN XY:

135090

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.367

Gnomad ASJ exome

AF:

0.467

Gnomad EAS exome

AF:

0.415

Gnomad SAS exome

AF:

0.427

Gnomad FIN exome

AF:

0.399

Gnomad NFE exome

AF:

0.337

Gnomad OTH exome

AF:

0.361

GnomAD4 exome

AF:

0.333

AC:

487181

AN:

1460848

Hom.:

83862

Cov.:

AF XY:

0.338

AC XY:

245420

AN XY:

726756

show subpopulations

Gnomad4 AFR exome

AF:

0.116

Gnomad4 AMR exome

AF:

0.367

Gnomad4 ASJ exome

AF:

0.469

Gnomad4 EAS exome

AF:

0.464

Gnomad4 SAS exome

AF:

0.421

Gnomad4 FIN exome

AF:

0.387

Gnomad4 NFE exome

AF:

0.320

Gnomad4 OTH exome

AF:

0.341

GnomAD4 genome

AF:

0.289

AC:

43847

AN:

151952

Hom.:

7186

Cov.:

AF XY:

0.298

AC XY:

22137

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.125

Gnomad4 AMR

AF:

0.344

Gnomad4 ASJ

AF:

0.458

Gnomad4 EAS

AF:

0.411

Gnomad4 SAS

AF:

0.416

Gnomad4 FIN

AF:

0.404

Gnomad4 NFE

AF:

0.328

Gnomad4 OTH

AF:

0.317

Alfa

AF:

0.327

Hom.:

9956

Bravo

AF:

0.274

TwinsUK

AF:

0.316

AC:

1170

ALSPAC

AF:

0.318

AC:

1226

ESP6500AA

AF:

0.121

AC:

532

ESP6500EA

AF:

0.335

AC:

2881

ExAC

AF:

0.348

AC:

42182

Asia WGS

AF:

0.408

AC:

1414

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:15Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 3

Pathogenic:1Benign:5

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

- -

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs1169288 with MODY3. This variant is found to be a potent moderate impact variant with a CADD score of 22.4 and sufficient scientific evidence to support the reported classification. Though this is seen to be a tolerated variant as per other insilico scores, this is reported more frequently in MODY cases as per recent evidence. -

Mar 01, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:4Other:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Nov 18, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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. -

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

- -

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

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria and response to sulfonylureas.However, evidence shows association of rs1169288 with T2DM and further clinical validation is required in MODY cases. -

Maturity onset diabetes mellitus in young

Benign:1

Aug 19, 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. -

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

- -

Insulin resistance, susceptibility to

Other:1

Jun 01, 2003

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

SERUM HDL CHOLESTEROL LEVEL, MODIFIER OF

Other:1

Jun 01, 2003

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.62

.;D;T;D;T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.019

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.55

T;T;T;T;T;T

MetaRNN

Benign

0.0012

T;T;T;T;T;T

MetaSVM

Benign

-1.2

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.92

N;.;.;.;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.082

T;.;.;.;T;T

Sift4G

Benign

0.088

T;T;T;T;T;T

Polyphen

0.020

.;.;.;.;.;B

Vest4

0.24

MPC

0.66

ClinPred

0.020

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.64

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