chrX-108668435-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_033380.3(COL4A5):c.3721G>T(p.Gly1241Cys) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1241D) has been classified as Pathogenic.
Frequency
Consequence
NM_033380.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.3721G>T | p.Gly1241Cys | missense_variant | 41/53 | ENST00000328300.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.3721G>T | p.Gly1241Cys | missense_variant | 41/53 | 1 | NM_033380.3 | ||
COL4A5 | ENST00000361603.7 | c.3721G>T | p.Gly1241Cys | missense_variant | 41/51 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
X-linked Alport syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 14, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Sep 25, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 07, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 26, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly1241 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 20378821; Invitae), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL4A5 protein function. ClinVar contains an entry for this variant (Variation ID: 24676). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 7599631; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 1241 of the COL4A5 protein (p.Gly1241Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at