X-108440182-TTGGGGGCA-T

Position:

• chrX-108440182-TTGGGGGCA-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_033380.3(COL4A5):​c.58_65del​(p.Trp20AlafsTer17) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 20)
• Consequence: COL4A5 NM_033380.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.18

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 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 870 pathogenic variants in the truncated region.
• PP5: Variant X-108440182-TTGGGGGCA-T is Pathogenic according to our data. Variant chrX-108440182-TTGGGGGCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 1458786.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.58_65del	p.Trp20AlafsTer17	frameshift_variant	1/53	ENST00000328300.11
COL4A5	NM_000495.5	c.58_65del	p.Trp20AlafsTer17	frameshift_variant	1/51
COL4A5	XM_047441811.1	c.58_65del	p.Trp20AlafsTer17	frameshift_variant	1/42
COL4A5	XM_047441810.1	c.-319_-312del		5_prime_UTR_variant	1/54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.58_65del	p.Trp20AlafsTer17	frameshift_variant	1/53	1	NM_033380.3

Frequencies

GnomAD3 genomes Cov.: 20

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with COL4A5-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp20Alafs*17) in the COL4A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-107683412;