rs104886443

Positions:

• chrX-108578361-TAG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033380.3(COL4A5):​c.761_762del​(p.Glu254ValfsTer11) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.96

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 18 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-108578361-TAG-T is Pathogenic according to our data. Variant chrX-108578361-TAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 587259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108578361-TAG-T is described in Lovd as [Pathogenic]. Variant chrX-108578361-TAG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.761_762del	p.Glu254ValfsTer11	frameshift_variant	13/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.761_762del	p.Glu254ValfsTer11	frameshift_variant	13/53	1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000361603.7	c.761_762del	p.Glu254ValfsTer11	frameshift_variant	13/51	2		ENSP00000354505	P1

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 18, 2022

This sequence change creates a premature translational stop signal (p.Glu254Valfs*11) 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). For these reasons, this variant has been classified as Pathogenic. This variant is also known as Glu254-->frameshift. This premature translational stop signal has been observed in individual(s) with clinical features of Alport syndrome (PMID: 8738805, 33040356). This variant is not present in population databases (gnomAD no frequency). -

X-linked Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Dec 20, 2018

- -

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: rs104886443; hg19: chrX-107821591;