rs2464195

Positions:

Variant summary

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

The NM_000545.8(HNF1A):c.1501+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,601,934 control chromosomes in the GnomAD database, including 110,205 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.32 ( 8637 hom., cov: 33)

Exomes 𝑓: 0.37 ( 101568 hom. )

Consequence

HNF1A
NM_000545.8 splice_region, intron

Scores

Splicing: ADA: 0.00001420

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9O:1

Conservation

PhyloP100: -2.15

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.2227126E-5).

BP6

Variant 12-120997672-G-A is Benign according to our data. Variant chr12-120997672-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129231.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Uncertain_significance=1, Benign=8}. Variant chr12-120997672-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
HNF1A	NM_000545.8 linkuse as main transcript	c.1501+7G>A	splice_region_variant, intron_variant	ENST00000257555.11
HNF1A	NM_001306179.2 linkuse as main transcript	c.1501+7G>A	splice_region_variant, intron_variant
HNF1A	NM_001406915.1 linkuse as main transcript	c.1309+930G>A	intron_variant
HNF1A	XM_024449168.2 linkuse as main transcript	c.1501+7G>A	splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.1501+7G>A		splice_region_variant, intron_variant		1	NM_000545.8	P4

Frequencies

GnomAD3 genomes

AF:

0.318

AC:

48276

AN:

152006

Hom.:

8635

Cov.:

show subpopulations

Gnomad AFR

AF:

0.145

Gnomad AMI

AF:

0.379

Gnomad AMR

AF:

0.392

Gnomad ASJ

AF:

0.503

Gnomad EAS

AF:

0.491

Gnomad SAS

AF:

0.514

Gnomad FIN

AF:

0.384

Gnomad MID

AF:

0.585

Gnomad NFE

AF:

0.356

Gnomad OTH

AF:

0.365

GnomAD3 exomes

AF:

0.390

AC:

90608

AN:

232434

Hom.:

18320

AF XY:

0.401

AC XY:

50497

AN XY:

126044

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.399

Gnomad ASJ exome

AF:

0.501

Gnomad EAS exome

AF:

0.485

Gnomad SAS exome

AF:

0.521

Gnomad FIN exome

AF:

0.372

Gnomad NFE exome

AF:

0.364

Gnomad OTH exome

AF:

0.393

GnomAD4 exome

AF:

0.368

AC:

533834

AN:

1449810

Hom.:

101568

Cov.:

AF XY:

0.374

AC XY:

269555

AN XY:

720574

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.403

Gnomad4 ASJ exome

AF:

0.506

Gnomad4 EAS exome

AF:

0.524

Gnomad4 SAS exome

AF:

0.517

Gnomad4 FIN exome

AF:

0.365

Gnomad4 NFE exome

AF:

0.352

Gnomad4 OTH exome

AF:

0.378

GnomAD4 genome

AF:

0.317

AC:

48277

AN:

152124

Hom.:

8637

Cov.:

AF XY:

0.326

AC XY:

24281

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.144

Gnomad4 AMR

AF:

0.392

Gnomad4 ASJ

AF:

0.503

Gnomad4 EAS

AF:

0.491

Gnomad4 SAS

AF:

0.513

Gnomad4 FIN

AF:

0.384

Gnomad4 NFE

AF:

0.356

Gnomad4 OTH

AF:

0.371

Alfa

AF:

0.342

Hom.:

4111

Bravo

AF:

0.309

TwinsUK

AF:

0.353

AC:

1308

ALSPAC

AF:

0.356

AC:

1372

ESP6500AA

AF:

0.141

AC:

622

ESP6500EA

AF:

0.366

AC:

3150

ExAC

AF:

0.373

AC:

45188

Asia WGS

AF:

0.477

AC:

1654

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

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 01, 2024	- -

Maturity-onset diabetes of the young type 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Type 2 diabetes mellitus

Uncertain:1

Uncertain significance, 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 multiple cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, no sufficient evidence is found to support association of rs2464195 with T2DM or MODY. -

Maturity onset diabetes mellitus in young

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2014

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

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.92

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.055

DANN

Benign

0.57

DEOGEN2

Benign

0.23

Eigen

Benign

-1.8

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.43

MetaRNN

Benign

0.000022

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

P;P;P;P

Sift4G

Benign

0.23

Vest4

0.047

ClinPred

0.019

GERP RS

-9.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.0020

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