rs2464195

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000535955.5(HNF1A):n.224G>A variant causes a non coding transcript exon 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. 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
ENST00000535955.5 non_coding_transcript_exon

Scores

Splicing: ADA: 0.00001420

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10O:1

Conservation

PhyloP100: -2.15

Publications

44 publications found

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 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)

HNF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 129231.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
HNF1A	NM_000545.8 link	c.1501+7G>A	splice_region_variant, intron_variant	Intron 7 of 9	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 link	c.1501+7G>A	splice_region_variant, intron_variant	Intron 7 of 9		NP_001293108.2
HNF1A	NM_001406915.1 link	c.1309+930G>A	intron_variant	Intron 6 of 8		NP_001393844.1
HNF1A	XM_024449168.2 link	c.1501+7G>A	splice_region_variant, intron_variant	Intron 7 of 8		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.1501+7G>A		splice_region_variant, intron_variant	Intron 7 of 9	1	NM_000545.8	ENSP00000257555.5

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

GnomAD2 exomes

AF:

0.390

AC:

90608

AN:

232434

AF XY:

0.401

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 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

African (AFR)

AF:

0.136

AC:

4506

AN:

33208

American (AMR)

AF:

0.403

AC:

17419

AN:

43270

Ashkenazi Jewish (ASJ)

AF:

0.506

AC:

13113

AN:

25904

East Asian (EAS)

AF:

0.524

AC:

20442

AN:

38998

South Asian (SAS)

AF:

0.517

AC:

43850

AN:

84828

European-Finnish (FIN)

AF:

0.365

AC:

19137

AN:

52456

Middle Eastern (MID)

AF:

0.553

AC:

3182

AN:

5754

European-Non Finnish (NFE)

AF:

0.352

AC:

389523

AN:

1105422

Other (OTH)

AF:

0.378

AC:

22662

AN:

59970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

17486

34972

52458

69944

87430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12492

24984

37476

49968

62460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.317

AC:

48277

AN:

152124

Hom.:

8637

Cov.:

AF XY:

0.326

AC XY:

24281

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.144

AC:

5999

AN:

41530

American (AMR)

AF:

0.392

AC:

5991

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.503

AC:

1743

AN:

3468

East Asian (EAS)

AF:

0.491

AC:

2535

AN:

5168

South Asian (SAS)

AF:

0.513

AC:

2477

AN:

4826

European-Finnish (FIN)

AF:

0.384

AC:

4061

AN:

10564

Middle Eastern (MID)

AF:

0.575

AC:

169

AN:

294

European-Non Finnish (NFE)

AF:

0.356

AC:

24177

AN:

67968

Other (OTH)

AF:

0.371

AC:

782

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1611

3222

4834

6445

8056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

502

1004

1506

2008

2510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.340

Hom.:

4123

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:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

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

- -

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. -

Oct 22, 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. -

Maturity-onset diabetes of the young type 3

Benign:3

Jan 13, 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

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Type 2 diabetes mellitus

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

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 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. -

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

Dec 08, 2014

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

0.077

BayesDel_addAF

Benign

-0.92

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.055

(source)

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

PhyloP100

-2.1

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over