Variant 12-120978797-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate

The NM_000545.8(HNF1A):c.29C>G(p.Thr10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign 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. T10M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.46

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a helix (size 15) in uniprot entity HNF1A_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000545.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-120978797-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.20703882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HNF1A	NM_000545.8 linkuse as main transcript	c.29C>G	p.Thr10Arg	missense_variant	1/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 linkuse as main transcript	c.29C>G	p.Thr10Arg	missense_variant	1/10		NP_001293108.2
HNF1A	NM_001406915.1 linkuse as main transcript	c.29C>G	p.Thr10Arg	missense_variant	1/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.29C>G	p.Thr10Arg	missense_variant	1/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.29C>G	p.Thr10Arg	missense_variant	1/10	1	NM_000545.8	ENSP00000257555	P4
HNF1A-AS1	ENST00000619441.1 linkuse as main transcript	n.128+1847G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460820

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726738

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Uncertain

0.48

.;T;T;T;T;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.79

T;T;T;T;T;T

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.21

T;T;T;T;T;T

MetaSVM

Uncertain

0.0025

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

0.22

N;.;.;.;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.56

T;.;.;.;T;T

Sift4G

Benign

0.83

T;T;T;T;T;T

Polyphen

0.0040

.;.;.;.;.;B

Vest4

0.16

MutPred

0.51

Gain of MoRF binding (P = 0.0173);Gain of MoRF binding (P = 0.0173);Gain of MoRF binding (P = 0.0173);Gain of MoRF binding (P = 0.0173);Gain of MoRF binding (P = 0.0173);Gain of MoRF binding (P = 0.0173);

MVP

0.83

MPC

0.19

ClinPred

0.39

GERP RS

3.4

gMVP

0.71

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