chr12-120978769-A-G
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>G(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 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-G is Pathogenic according to our data. Variant chr12-120978769-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 36814.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>G | p.Met1? | start_lost | 1/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.1A>G | p.Met1? | start_lost | 1/10 | ||
HNF1A | NM_001406915.1 | c.1A>G | p.Met1? | start_lost | 1/9 | ||
HNF1A | XM_024449168.2 | c.1A>G | p.Met1? | start_lost | 1/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1A>G | p.Met1? | start_lost | 1/10 | 1 | NM_000545.8 | P4 | |
HNF1A-AS1 | ENST00000619441.1 | n.128+1875T>C | 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: Pathogenic
Submissions summary: Pathogenic:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 03, 2023 | This sequence change affects the initiator methionine of the HNF1A mRNA. The next in-frame methionine is located at codon 118. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HNF1A protein in which other variant(s) (p.Leu107Arg) have been determined to be pathogenic (PMID: 9166684). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 36814). This variant has not been reported in the literature in individuals affected with HNF1A-related conditions. This variant is not present in population databases (gnomAD no frequency). - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 21, 2021 | This variant results in the loss of the initiator methionine codon and is predicted to interfere with protein translation. If translation were to begin at the next methionine codon, p.Met118, the dimerization domain would be lost. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Three different variants at this initiator codon have been reported in the literature. - |
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Mar 04, 2022 | The c.1A>G variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1Val) 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; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.1A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/2021): PVS1, PM2_Supporting, PP4_Moderate - |
Maturity onset diabetes mellitus in young Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs193922592 with MODY3. - |
Maturity-onset diabetes of the young type 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
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;.;.;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
0.81
.;.;.;.;.;P
Vest4
MutPred
Gain of ubiquitination at K4 (P = 0.1432);Gain of ubiquitination at K4 (P = 0.1432);Gain of ubiquitination at K4 (P = 0.1432);Gain of ubiquitination at K4 (P = 0.1432);Gain of ubiquitination at K4 (P = 0.1432);Gain of ubiquitination at K4 (P = 0.1432);
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