rs397514263
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2
The NM_005235.3(ERBB4):c.3823C>T(p.Arg1275Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1275Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_005235.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERBB4 | NM_005235.3 | c.3823C>T | p.Arg1275Trp | missense_variant | 28/28 | ENST00000342788.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERBB4 | ENST00000342788.9 | c.3823C>T | p.Arg1275Trp | missense_variant | 28/28 | 1 | NM_005235.3 | P4 | |
ERBB4 | ENST00000436443.5 | c.3775C>T | p.Arg1259Trp | missense_variant | 27/27 | 1 | A1 | ||
ERBB4 | ENST00000260943.11 | c.3745C>T | p.Arg1249Trp | missense_variant | 27/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251046Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135678
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461794Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727196
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74300
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 13, 2022 | This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 24119685). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ERBB4 function (PMID: 24119685). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 64626). This variant is present in population databases (rs397514263, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1275 of the ERBB4 protein (p.Arg1275Trp). - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | ERBB4: PM2:Supporting, PS2:Supporting, PS3:Supporting, PS4:Supporting - |
Pathogenic, no assertion criteria provided | literature only | Department of Neurology The University of Tokyo, Graduate School of Medicine | - | - - |
Amyotrophic lateral sclerosis type 19 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 07, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at