12-120999418-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000545.8(HNF1A):c.1623+29T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 1,613,794 control chromosomes in the GnomAD database, including 531,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 44840 hom., cov: 32)

Exomes 𝑓: 0.81 ( 486392 hom. )

Consequence

HNF1A
NM_000545.8 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -3.77

Publications

30 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.387669E-7).

BP6

Variant 12-120999418-T-C is Benign according to our data. Variant chr12-120999418-T-C is described in ClinVar as Benign. ClinVar VariationId is 135505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.866 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.1623+29T>C	intron	N/A	NP_000536.6
HNF1A	NM_001306179.2		c.1623+29T>C	intron	N/A	NP_001293108.2	F5H0K0
HNF1A	NM_001406915.1		c.1431+29T>C	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.1623+29T>C	intron	N/A	ENSP00000257555.5	P20823-1
HNF1A	ENST00000544413.2	TSL:1	c.1623+29T>C	intron	N/A	ENSP00000438804.1	F5H0K0
HNF1A	ENST00000540108.1	TSL:1	n.*1063+29T>C	intron	N/A	ENSP00000445445.1	P20823-8

Frequencies

GnomAD3 genomes

AF:

0.759

AC:

115468

AN:

152032

Hom.:

44808

Cov.:

show subpopulations

Gnomad AFR

AF:

0.586

Gnomad AMI

AF:

0.772

Gnomad AMR

AF:

0.878

Gnomad ASJ

AF:

0.876

Gnomad EAS

AF:

0.870

Gnomad SAS

AF:

0.843

Gnomad FIN

AF:

0.810

Gnomad MID

AF:

0.930

Gnomad NFE

AF:

0.808

Gnomad OTH

AF:

0.810

GnomAD2 exomes

AF:

0.823

AC:

206387

AN:

250922

AF XY:

0.824

show subpopulations

Gnomad AFR exome

AF:

0.573

Gnomad AMR exome

AF:

0.921

Gnomad ASJ exome

AF:

0.879

Gnomad EAS exome

AF:

0.874

Gnomad FIN exome

AF:

0.801

Gnomad NFE exome

AF:

0.815

Gnomad OTH exome

AF:

0.837

GnomAD4 exome

AF:

0.814

AC:

1190214

AN:

1461644

Hom.:

486392

Cov.:

AF XY:

0.815

AC XY:

592744

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.578

AC:

19354

AN:

33478

American (AMR)

AF:

0.914

AC:

40888

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.879

AC:

22979

AN:

26132

East Asian (EAS)

AF:

0.892

AC:

35423

AN:

39700

South Asian (SAS)

AF:

0.833

AC:

71862

AN:

86254

European-Finnish (FIN)

AF:

0.808

AC:

42999

AN:

53214

Middle Eastern (MID)

AF:

0.869

AC:

5014

AN:

5768

European-Non Finnish (NFE)

AF:

0.812

AC:

902566

AN:

1111984

Other (OTH)

AF:

0.814

AC:

49129

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

15765

31529

47294

63058

78823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20896

41792

62688

83584

104480

<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:

0.759

AC:

115548

AN:

152150

Hom.:

44840

Cov.:

AF XY:

0.763

AC XY:

56764

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.586

AC:

24336

AN:

41496

American (AMR)

AF:

0.878

AC:

13437

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.876

AC:

3042

AN:

3472

East Asian (EAS)

AF:

0.870

AC:

4490

AN:

5162

South Asian (SAS)

AF:

0.842

AC:

4062

AN:

4824

European-Finnish (FIN)

AF:

0.810

AC:

8586

AN:

10602

Middle Eastern (MID)

AF:

0.918

AC:

270

AN:

294

European-Non Finnish (NFE)

AF:

0.808

AC:

54907

AN:

67974

Other (OTH)

AF:

0.812

AC:

1714

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1378

2756

4133

5511

6889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<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:

0.747

Hom.:

17880

Bravo

AF:

0.759

TwinsUK

AF:

0.813

AC:

3016

ALSPAC

AF:

0.817

AC:

3148

ESP6500AA

AF:

0.600

AC:

2645

ESP6500EA

AF:

0.817

AC:

7030

ExAC

AF:

0.814

AC:

98827

Asia WGS

AF:

0.876

AC:

3048

AN:

3478

EpiCase

AF:

0.814

EpiControl

AF:

0.817

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Maturity-onset diabetes of the young (1)

Maturity-onset diabetes of the young type 3 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.20

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.23

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.18

MetaRNN

Benign

8.4e-7

MetaSVM

Benign

-0.98

PhyloP100

-3.8

PROVEAN

Benign

0.20

REVEL

Uncertain

0.31

Sift

Benign

0.046

Sift4G

Benign

0.37

Vest4

0.021

ClinPred

0.031

GERP RS

-11

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

SpliceAI score (max)

0.020

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