rs2464196

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP6_Strong

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 cumulative frequency of 0.309 (AC=497,531) in the gnomAD database across 1,612,298 control chromosomes, including 80,461 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.517. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S487G: Uncertain_significance (ClinVar VariationId 3237446, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.27 ( 6416 hom., cov: 32)

Exomes 𝑓: 0.31 ( 74045 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.05

Publications

160 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, STRONG Submitted by: PanelApp Australia, ClinGen
type 1 diabetes mellitus 20
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine
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: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
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

new If you want to explore the variant's impact on the transcript NM_000545.8, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Specifications for HNF1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -12 points.

BP6

ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (15/15 total B/LB).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5171 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000545.8. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNF1A	NM_000545.8	MANE Select	c.1460G>A	p.Ser487Asn	missense	Exon 7 of 10	NP_000536.6
HNF1A	NM_001306179.2		c.1460G>A	p.Ser487Asn	missense	Exon 7 of 10	NP_001293108.2	F5H0K0
HNF1A	NM_001406915.1		c.1309+882G>A		intron	N/A	NP_001393844.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1460G>A	p.Ser487Asn	missense	Exon 7 of 10	ENSP00000257555.5	P20823-1
HNF1A	ENST00000544413.2	TSL:1	c.1460G>A	p.Ser487Asn	missense	Exon 7 of 10	ENSP00000438804.1	F5H0K0
HNF1A	ENST00000538646.5	TSL:1	n.*436G>A		3_prime_UTR	Exon 6 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes

AF:

0.273

AC:

41508

AN:

152026

Hom.:

6414

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.316

AC XY:

229707

AN XY:

726350

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

18777

37554

56332

75109

93886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10956

21912

32868

43824

54780

<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:

0.273

AC:

41510

AN:

152144

Hom.:

6416

Cov.:

AF XY:

0.280

AC XY:

20838

AN XY:

74374

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1482

2964

4446

5928

7410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

442

884

1326

1768

2210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.267

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.299

AC:

171231

AN:

571728

Hom.:

27359

Local populations

ABraOM SABE-WGS-1171

AF:

0.289

AC:

677

AN:

2342

Hom.:

102

ChinaMAP Phase 1

AF:

0.474

Denmark Genome

AF:

0.303

AC:

AN:

300

ESP6500 (Exome Variant Server)

AF:

0.247

AC:

3217

AN:

13006

show subpopulations

European American

AF:

0.311

AC:

2676

AN:

8600

African American

AF:

0.123

AC:

541

AN:

4406

GenomeAsia100K

AF:

0.419

AC:

1452

AN:

3478

show subpopulations

Oceania

AF:

0.885

AC:

131

AN:

148

Hom.:

North-East Asia

AF:

0.567

AC:

398

AN:

702

Hom.:

109

South-East Asia

AF:

0.363

AC:

251

AN:

692

Hom.:

South Asia

AF:

0.374

AC:

541

AN:

1448

Hom.:

102

Africa

AF:

0.115

AC:

AN:

208

Hom.:

America

AF:

0.308

AC:

AN:

Hom.:

West Eurasia

AF:

0.399

AC:

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.551

AC:

3983

AN:

7234

Qatari Genome

AF:

0.531

AC:

1047

AN:

1972

Turkish Variome

AF:

0.429

AC:

2754

AN:

6422

Hom.:

598

UK10K

AF:

0.297

AC:

2246

AN:

7562

show subpopulations

TwinsUK

AF:

0.294

AC:

1051

AN:

3574

ALSPAC

AF:

0.300

AC:

1156

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.485

AC:

4347

AN:

8960

Hom.:

1083

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

3214 / 11066AF: 0.290439

5095 / 17260AF: 0.295191

BipEx

(Bipolar disorder (including schizoaffective))

8524 / 28420AF: 0.299930

8496 / 28844AF: 0.294550

Epi25

(Epilepsy)

12791 / 41958AF: 0.304852

20015 / 66888AF: 0.299232

SCHEMA

(Schizophrenia)

55621 / 155870AF: 0.356842

87597 / 252194AF: 0.347340

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Maturity-onset diabetes of the young type 3 (3)

not provided (3)

Maturity-onset diabetes of the young (1)

Nonpapillary renal cell carcinoma (1)

Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

PhyloP100

1.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.61

REVEL

Uncertain

0.35

Sift

Benign

0.11

Sift4G

Benign

0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

popEVE

Benign

-3.1

(source)

VESM-3B

Benign

-4.3

(source)

AlphaGenome AVI

Uncertain

(source)

GPN-Star LLR

-3.6

(source)

GPN-Star score

3.6

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.0

(source)

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over