X-108624282-AG-A

Position:

• chrX-108624282-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_033380.3(COL4A5):​c.2965del​(p.Asp989ThrfsTer7) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in Lovd as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: COL4A5 NM_033380.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.42

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108624282-AG-A is Pathogenic according to our data. Variant chrX-108624282-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2965del	p.Asp989ThrfsTer7	frameshift_variant	34/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2965del	p.Asp989ThrfsTer7	frameshift_variant	34/53	1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000483338.1	c.1789del	p.Asp597ThrfsTer7	frameshift_variant	18/20	1		ENSP00000495685
COL4A5	ENST00000361603.7	c.2965del	p.Asp989ThrfsTer7	frameshift_variant	34/51	2		ENSP00000354505	P1
COL4A5	ENST00000505728.1	c.198del	p.Asp67ThrfsTer7	frameshift_variant	2/5	3		ENSP00000424137

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104886206; hg19: chrX-107867512;