rs104886141
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_033380.3(COL4A5):c.1861G>A(p.Gly621Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,894 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. G621D) has been classified as Pathogenic.
Frequency
Consequence
NM_033380.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.1861G>A | p.Gly621Ser | missense_variant | 25/53 | ENST00000328300.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.1861G>A | p.Gly621Ser | missense_variant | 25/53 | 1 | NM_033380.3 | ||
COL4A5 | ENST00000483338.1 | c.685G>A | p.Gly229Ser | missense_variant | 9/20 | 1 | |||
COL4A5 | ENST00000361603.7 | c.1861G>A | p.Gly621Ser | missense_variant | 25/51 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome AF: 9.12e-7 AC: 1AN: 1096894Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 362370
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 26, 2019 | Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur; this glycine flanks an interruption within the triple helical region. Missense substitution of a canonical Glycine residue in a Gly-X-Y motif in the triple helical region often disrupts normal protein folding and function; however this particular collagen gene is known to have several naturally occurring interruptions of the Gly-X-Y repeats and we cannot precisely predict the consequences of this change; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at