12-120979061-C-T

Variant names:

Variant summary

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

The NM_001306179.2(HNF1A):c.293C>T(p.Ala98Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,611,476 control chromosomes in the GnomAD database, including 921 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A98T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.022 ( 52 hom., cov: 32)

Exomes 𝑓: 0.030 ( 869 hom. )

Consequence

HNF1A
NM_001306179.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: 7.35

Publications

107 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 links:

HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

HNF1A-AS1 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=0.0042442083).

BP6

Variant 12-120979061-C-T is Benign according to our data. Variant chr12-120979061-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0591 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001306179.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HNF1A	NM_000545.8	MANE Select	c.293C>T	p.Ala98Val	missense	Exon 1 of 10	NP_000536.6
HNF1A	NM_001306179.2		c.293C>T	p.Ala98Val	missense	Exon 1 of 10	NP_001293108.2
HNF1A	NM_001406915.1		c.293C>T	p.Ala98Val	missense	Exon 1 of 9	NP_001393844.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.293C>T	p.Ala98Val	missense	Exon 1 of 10	ENSP00000257555.5
HNF1A	ENST00000544413.2	TSL:1	c.293C>T	p.Ala98Val	missense	Exon 1 of 10	ENSP00000438804.1
HNF1A	ENST00000538646.5	TSL:1	n.293C>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3342

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00543

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.0135

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0656

Gnomad FIN

AF:

0.0475

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0278

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.0290

AC:

6974

AN:

240478

AF XY:

0.0322

show subpopulations

Gnomad AFR exome

AF:

0.00543

Gnomad AMR exome

AF:

0.0115

Gnomad ASJ exome

AF:

0.0361

Gnomad EAS exome

AF:

0.0000551

Gnomad FIN exome

AF:

0.0416

Gnomad NFE exome

AF:

0.0295

Gnomad OTH exome

AF:

0.0277

GnomAD4 exome

AF:

0.0300

AC:

43743

AN:

1459166

Hom.:

869

Cov.:

AF XY:

0.0313

AC XY:

22689

AN XY:

725618

show subpopulations

African (AFR)

AF:

0.00487

AC:

163

AN:

33446

American (AMR)

AF:

0.0121

AC:

537

AN:

44424

Ashkenazi Jewish (ASJ)

AF:

0.0348

AC:

906

AN:

26046

East Asian (EAS)

AF:

0.000101

AC:

AN:

39646

South Asian (SAS)

AF:

0.0670

AC:

5742

AN:

85692

European-Finnish (FIN)

AF:

0.0427

AC:

2258

AN:

52940

Middle Eastern (MID)

AF:

0.0428

AC:

246

AN:

5742

European-Non Finnish (NFE)

AF:

0.0290

AC:

32228

AN:

1110948

Other (OTH)

AF:

0.0275

AC:

1659

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2522

5044

7567

10089

12611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1222

2444

3666

4888

6110

<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:

0.0219

AC:

3337

AN:

152310

Hom.:

Cov.:

AF XY:

0.0232

AC XY:

1725

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00544

AC:

226

AN:

41576

American (AMR)

AF:

0.0134

AC:

205

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0320

AC:

111

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0650

AC:

314

AN:

4830

European-Finnish (FIN)

AF:

0.0475

AC:

504

AN:

10618

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0278

AC:

1893

AN:

68016

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

174

348

523

697

871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0268

Hom.:

185

Bravo

AF:

0.0181

TwinsUK

AF:

0.0275

AC:

102

ALSPAC

AF:

0.0270

AC:

104

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0257

AC:

220

ExAC

AF:

0.0288

AC:

3492

Asia WGS

AF:

0.0240

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (3)

Maturity onset diabetes mellitus in young (2)

Maturity-onset diabetes of the young type 3 (2)

Monogenic diabetes (1)

Nonpapillary renal cell carcinoma (1)

Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0042

MetaSVM

Uncertain

0.40

PhyloP100

7.3

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.60

Sift

Benign

0.063

Sift4G

Benign

0.090

Polyphen

0.21

Vest4

0.46

MPC

0.27

ClinPred

0.086

GERP RS

4.5

PromoterAI

-0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

gMVP

0.90

Mutation Taster

=70/30

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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