rs1553695389
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000092.5(COL4A4):c.428G>T(p.Gly143Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,712 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G143G) has been classified as Likely benign.
Frequency
Consequence
NM_000092.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A4 | NM_000092.5 | c.428G>T | p.Gly143Val | missense_variant | 7/48 | ENST00000396625.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A4 | ENST00000396625.5 | c.428G>T | p.Gly143Val | missense_variant | 7/48 | 5 | NM_000092.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461712Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727174
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2023 | ClinVar contains an entry for this variant (Variation ID: 557549). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 143 of the COL4A4 protein (p.Gly143Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 25514610, 28632965). 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 COL4A4 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Diffuse mesangial sclerosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | May 18, 2022 | - - |
Autosomal recessive Alport syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 29, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at