rs142204928
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_175914.5(HNF4A):c.439G>A(p.Val147Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000959 in 1,614,194 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_175914.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF4A | NM_175914.5 | c.439G>A | p.Val147Ile | missense_variant | 5/10 | ENST00000316673.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF4A | ENST00000316673.9 | c.439G>A | p.Val147Ile | missense_variant | 5/10 | 1 | NM_175914.5 |
Frequencies
GnomAD3 genomes ? AF: 0.000723 AC: 110AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00201 AC: 505AN: 251390Hom.: 6 AF XY: 0.00241 AC XY: 327AN XY: 135866
GnomAD4 exome AF: 0.000984 AC: 1438AN: 1461860Hom.: 20 Cov.: 33 AF XY: 0.00133 AC XY: 968AN XY: 727226
GnomAD4 genome ? AF: 0.000722 AC: 110AN: 152334Hom.: 0 Cov.: 32 AF XY: 0.000832 AC XY: 62AN XY: 74502
ClinVar
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | HNF4A: BP4, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 13, 2020 | This variant is associated with the following publications: (PMID: 32621647, 31216263, 25041077, 27080136, 27535533, 27810688, 15281001, 24097065) - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 14, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | May 02, 2019 | - - |
Type 2 diabetes mellitus Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | The heterozygous p.Val147Ile variant in HNF4A has been identified in 3 Philippino siblings from 1 family with maturity onset diabetes of the young and 2 individuals without diabetes mellitus (PMID: 15281001, 24097065), but has also been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Please note that individuals in ExAC may have type II diabetes. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant diabetes mellitus type 2. - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Maturity-onset diabetes of the young type 1 Benign:1Other:1
not provided, no classification provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Familial hyperinsulinism Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Maturity onset diabetes mellitus in young Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 27, 2021 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at