X-108440173-CCT-C

Position:

• chrX-108440173-CCT-C

Variant summary

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

The NM_033380.3(COL4A5):​c.49_50del​(p.Leu17GlufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 20)
• Consequence: COL4A5 NM_033380.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.96

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 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-108440173-CCT-C is Pathogenic according to our data. Variant chrX-108440173-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 24228.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108440173-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.49_50del	p.Leu17GlufsTer22	frameshift_variant	1/53	ENST00000328300.11
COL4A5	NM_000495.5	c.49_50del	p.Leu17GlufsTer22	frameshift_variant	1/51
COL4A5	XM_047441811.1	c.49_50del	p.Leu17GlufsTer22	frameshift_variant	1/42
COL4A5	XM_047441810.1	c.-328_-327del		5_prime_UTR_variant	1/54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.49_50del	p.Leu17GlufsTer22	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

research

Gharavi Laboratory, Columbia University

Sep 16, 2018

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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: rs104886427; hg19: chrX-107683403;