rs104886264
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Moderate
The NM_033380.3(COL4A5):c.3782G>A(p.Gly1261Glu) 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1261R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_033380.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.3782G>A | p.Gly1261Glu | missense_variant | 41/53 | ENST00000328300.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.3782G>A | p.Gly1261Glu | missense_variant | 41/53 | 1 | NM_033380.3 | ||
COL4A5 | ENST00000361603.7 | c.3782G>A | p.Gly1261Glu | missense_variant | 41/51 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2021 | This variant disrupts the p.Gly1261 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 28356090), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). 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. This variant has been observed in individual(s) with clinical features of Alport syndrome (PMID: 9848783, Invitae). ClinVar contains an entry for this variant (Variation ID: 24682). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 1261 of the COL4A5 protein (p.Gly1261Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at