rs193922592
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000545.8(HNF1A):c.1A>C(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Consequence
HNF1A
NM_000545.8 start_lost
NM_000545.8 start_lost
Scores
9
3
3
Clinical Significance
Conservation
PhyloP100: 7.33
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 Pathogenic. Variant got 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_000545.8 (HNF1A) was described as [Pathogenic] in ClinVar as 502525
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-120978769-A-C is Pathogenic according to our data. Variant chr12-120978769-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1342948.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1A>C | p.Met1? | start_lost | 1/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.1A>C | p.Met1? | start_lost | 1/10 | ||
HNF1A | NM_001406915.1 | c.1A>C | p.Met1? | start_lost | 1/9 | ||
HNF1A | XM_024449168.2 | c.1A>C | p.Met1? | start_lost | 1/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1A>C | p.Met1? | start_lost | 1/10 | 1 | NM_000545.8 | P4 | |
HNF1A-AS1 | ENST00000619441.1 | n.128+1875T>G | 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: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Monogenic diabetes Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Mar 04, 2022 | The c.1A>C variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1?) of NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1A>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
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
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D
PROVEAN
Benign
N;.;.;N;N;N
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;T;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
0.65
.;.;.;.;.;P
Vest4
MutPred
Loss of methylation at K4 (P = 0.0899);Loss of methylation at K4 (P = 0.0899);Loss of methylation at K4 (P = 0.0899);Loss of methylation at K4 (P = 0.0899);Loss of methylation at K4 (P = 0.0899);Loss of methylation at K4 (P = 0.0899);
MVP
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.