chr12-120978772-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000545.8(HNF1A):c.4G>A(p.Val2Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
HNF1A
NM_000545.8 missense
NM_000545.8 missense
Scores
6
7
4
Clinical Significance
Conservation
PhyloP100: 6.47
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000545.8
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.4G>A | p.Val2Ile | missense_variant | 1/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.4G>A | p.Val2Ile | missense_variant | 1/10 | ||
HNF1A | NM_001406915.1 | c.4G>A | p.Val2Ile | missense_variant | 1/9 | ||
HNF1A | XM_024449168.2 | c.4G>A | p.Val2Ile | missense_variant | 1/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.4G>A | p.Val2Ile | missense_variant | 1/10 | 1 | NM_000545.8 | P4 | |
HNF1A-AS1 | ENST00000619441.1 | n.128+1872C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 01, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HNF1A protein function. This variant has not been reported in the literature in individuals with HNF1A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 2 of the HNF1A protein (p.Val2Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Benign
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;.;.;T;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
0.85
.;.;.;.;.;P
Vest4
MutPred
Gain of catalytic residue at V2 (P = 0.0774);Gain of catalytic residue at V2 (P = 0.0774);Gain of catalytic residue at V2 (P = 0.0774);Gain of catalytic residue at V2 (P = 0.0774);Gain of catalytic residue at V2 (P = 0.0774);Gain of catalytic residue at V2 (P = 0.0774);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.