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 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: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.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF1A	NM_000545.8	MANE Select	c.1501+7G>A	splice_region intron	N/A	NP_000536.6
HNF1A	NM_001306179.2		c.1501+7G>A	splice_region intron	N/A	NP_001293108.2	F5H0K0
HNF1A	NM_001406915.1		c.1309+930G>A	intron	N/A	NP_001393844.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1501+7G>A	splice_region intron	N/A	ENSP00000257555.5	P20823-1
HNF1A	ENST00000544413.2	TSL:1	c.1501+7G>A	splice_region intron	N/A	ENSP00000438804.1	F5H0K0
HNF1A	ENST00000535955.5	TSL:1	n.224G>A	non_coding_transcript_exon	Exon 2 of 2

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not specified (4)

not provided (2)

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

0.077

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over