rs1169288

chr12-120978847-A-Cchr12-120978847-A-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BA1

The NM_000545(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 0.289 in 151834 control chromosomes in the gnomAD Genomes database, including 7184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting interpretations of pathogenicity (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I27S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.29 ( 7184 hom., cov: 32)

Exomes 𝑓: 0.35 ( 16580 hom. )

Consequence

HNF1A
NM_000545 missense

Scores

Clinical Significance

Conflicting interpretations of pathogenicity criteria provided, conflicting interpretations P:1B:12O:3

Conservation

PhyloP100: 3.21

Links

HNF1A (HGNC:11621):

HNF1A-AS1 (HGNC:26785):

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000545

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_interpretations_of_pathogenicity]. Clinvar id is 14937. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=11, Likely_pathogenic=1}. Variant chr12-120978847-A-C is described in Lovd as [Benign].

BA1

GnomAd highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HNF1A	NM_000545.8 linkuse as main transcript	c.79A>C	p.Ile27Leu	missense_variant	1/10	ENST00000257555.11
HNF1A	NM_001306179.2 linkuse as main transcript	c.79A>C	p.Ile27Leu	missense_variant	1/10
HNF1A	XM_024449168.2 linkuse as main transcript	c.79A>C	p.Ile27Leu	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.79A>C	p.Ile27Leu	missense_variant	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1 linkuse as main transcript	n.128+1797T>G		intron_variant, non_coding_transcript_variant		3

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

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

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: Conflicting interpretations of pathogenicity

Submissions summary: Pathogenic:1Benign:12Other:3

Revision: criteria provided, conflicting interpretations

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

not provided, no assertion provided	reference population	ITMI	Sep 19, 2013	- -
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. -
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	Eurofins Ntd Llc (ga)	Nov 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, PreventionGenetics	-	- -

Maturity-onset diabetes of the young type 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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	Mendelics	May 28, 2019	- -

Maturity onset diabetes mellitus in young

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 19, 2015	This alteration is classified as benign based on a combination of the following: 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. -
Likely pathogenic, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics Inc	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2022	- -

Type 2 diabetes mellitus

Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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. -

Nonpapillary renal cell carcinoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Insulin resistance, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

SERUM HDL CHOLESTEROL LEVEL, MODIFIER OF

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

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

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

MutationTaster

Benign

0.0043

P;P;P;P;P

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

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

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over