Variant 12-120997588-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000545.8(HNF1A):c.1424C>G(p.Pro475Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P475L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.83

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HNF1A	NM_000545.8 linkuse as main transcript	c.1424C>G	p.Pro475Arg	missense_variant	7/10	ENST00000257555.11
HNF1A	NM_001306179.2 linkuse as main transcript	c.1424C>G	p.Pro475Arg	missense_variant	7/10
HNF1A	XM_024449168.2 linkuse as main transcript	c.1424C>G	p.Pro475Arg	missense_variant	7/9
HNF1A	NM_001406915.1 linkuse as main transcript	c.1309+846C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.1424C>G	p.Pro475Arg	missense_variant	7/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461498

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.7

D;.;.;.;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

D;.;.;.;D;D

Sift4G

Uncertain

0.0090

D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;.;D

Vest4

0.79

MutPred

0.53

Loss of glycosylation at P475 (P = 0.0396);Loss of glycosylation at P475 (P = 0.0396);.;.;Loss of glycosylation at P475 (P = 0.0396);Loss of glycosylation at P475 (P = 0.0396);

MVP

0.88

MPC

0.50

ClinPred

0.99

GERP RS

4.5

gMVP

0.90

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over