chr20-44355806-T-C
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_175914.5(HNF4A):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,380 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
HNF4A
NM_175914.5 start_lost
NM_175914.5 start_lost
Scores
4
7
4
Clinical Significance
Conservation
PhyloP100: 4.66
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 1299751
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-44355806-T-C is Pathogenic according to our data. Variant chr20-44355806-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 689636.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF4A | NM_175914.5 | c.2T>C | p.Met1? | start_lost | 1/10 | ENST00000316673.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF4A | ENST00000316673.9 | c.2T>C | p.Met1? | start_lost | 1/10 | 1 | NM_175914.5 | ||
HNF4A | ENST00000457232.5 | c.2T>C | p.Met1? | start_lost | 1/10 | 1 | |||
HNF4A | ENST00000609795.5 | c.2T>C | p.Met1? | start_lost | 1/8 | 1 | |||
HNF4A | ENST00000609262.5 | c.-230T>C | 5_prime_UTR_variant | 1/4 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247240Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134596
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461380Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726960
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GnomAD4 genome ? Cov.: 32
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Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:2Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 02, 2019 | Has not been previously published as pathogenic or benign to our knowledge - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2023 | This sequence change affects the initiator methionine of the HNF4A mRNA. The next in-frame methionine is located at codon 71. This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of the initiator codon has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 21683639, 30977832). ClinVar contains an entry for this variant (Variation ID: 689636). This variant disrupts a region of the HNF4A protein in which other variant(s) (p.Arg63Trp) have been determined to be pathogenic (PMID: 20164212, 25819479, 28458902, 31875549). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Monogenic diabetes Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Jan 02, 2024 | The c.2T>C variant in the hepatic nuclear factor-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of 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_Strong; PMID: 23348805). This variant is only present in one copy in the Latino/Admixed American subpopulation in gnomAD v2.1.1 and therefore a Popmax FAF is unavailable. Still, the variant meets the ClinGen MDEP threshold for PM2_Supporting (gnomAD 2.1.1 Popmax FAF <= 1:333,000 (<= 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND <= 2 copies observed in ENF AND <= 1 copy in any other founder or non-founder population) (PM2_Supporting). This variant was identified in four unrelated individuals with non-autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). In summary, c.2T>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 2.0.0, approved 10/11/2023): PVS1_Strong, PS4_Moderate, PM2_Supporting. - |
Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young Uncertain:1
Uncertain significance, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jul 01, 2019 | ACMG codes: PVS1 - |
Maturity onset diabetes mellitus in young Other:1
Uncertain risk allele, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs1229650809 in MODY, yet. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PROVEAN
Benign
N;.;N
REVEL
Uncertain
Sift
Pathogenic
D;.;D
Sift4G
Benign
T;D;T
Polyphen
0.81, 0.60
.;P;P
Vest4
MutPred
Gain of glycosylation at M1 (P = 0.0041);Gain of glycosylation at M1 (P = 0.0041);Gain of glycosylation at M1 (P = 0.0041);
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