chr20-44355807-G-A
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_175914.5(HNF4A):c.3G>A(p.Met1?) variant causes a start lost change. 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
HNF4A
NM_175914.5 start_lost
NM_175914.5 start_lost
Scores
6
6
3
Clinical Significance
Conservation
PhyloP100: 5.87
Genes affected
HNF4A (HGNC:5024): (hepatocyte nuclear factor 4 alpha) The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]
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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_175914.5 (HNF4A) was described as [Likely_pathogenic] in ClinVar as 689636
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-44355807-G-A is Pathogenic according to our data. Variant chr20-44355807-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1299751.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr20-44355807-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF4A | NM_175914.5 | c.3G>A | p.Met1? | start_lost | 1/10 | ENST00000316673.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF4A | ENST00000316673.9 | c.3G>A | p.Met1? | start_lost | 1/10 | 1 | NM_175914.5 | ||
HNF4A | ENST00000457232.5 | c.3G>A | p.Met1? | start_lost | 1/10 | 1 | |||
HNF4A | ENST00000609795.5 | c.3G>A | p.Met1? | start_lost | 1/8 | 1 | |||
HNF4A | ENST00000609262.5 | c.-229G>A | 5_prime_UTR_variant | 1/4 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
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 | Apr 06, 2024 | The c.3G>A variant in the hepatocyte nuclear factor -4 alpha gene, HNF4A, results in a start loss at the initiation codon in NM_175914.4. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 23348805). In addition, 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 HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative diabetes autoantibodies (PP4_Moderate; PMID: 30977832, internal lab contributors). In summary, c.3G>A meets the criteria to be classified as Likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023: PVS1_Strong, PM2_Supporting, PP4_Moderate. - |
Maturity-onset diabetes of the young type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Exeter Molecular Genetics Laboratory | Oct 05, 2021 | The c.3G>A variant in the HNF4 homeobox A gene, HNF4A, results in the loss of the initiation codon (p.Met1?) in exon 1 of the pancreatic specific HNF4A isoform NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Moderate; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMID:21683639, PMID:30977832). However, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold. One of these individuals had a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; PMID:30977832). This variant also segregated with diabetes, with two informative meioses in the published family (PMID:21683639) but this is an insufficient number of meiosis to meet PP1 criteria. A different variant at that also results in the loss of the initiation codon has been identified by our laboratory and classified as likely pathogenic (PS1_Supporting). In summary, c.3G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied: PVS1_Moderate, PS1_Supporting, PP4_Moderate, PM2_Supporting. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PROVEAN
Benign
N;.;N
REVEL
Pathogenic
Sift
Pathogenic
D;.;D
Sift4G
Benign
T;T;T
Polyphen
0.66, 0.39
.;P;B
Vest4
MutPred
Gain of catalytic residue at S3 (P = 0.0992);Gain of catalytic residue at S3 (P = 0.0992);Gain of catalytic residue at S3 (P = 0.0992);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.