rs1556411578

Variant names:

• chrX-108595506-TAGGTGACAA-T
• rs1556411578
• NM_033380.3:c.1430_1438delAAGGTGACA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000328300.11(COL4A5):​c.1424-2_1430delAGGTGACAA​(p.Gly475fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. 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: 22)
• Consequence: COL4A5 ENST00000328300.11 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.27

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 12 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-108595506-TAGGTGACAA-T is Pathogenic according to our data. Variant chrX-108595506-TAGGTGACAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 523544.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1430_1438delAAGGTGACA	p.Lys477_Asp479del	disruptive_inframe_deletion	Exon 22 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1424-2_1430delAGGTGACAA	p.Gly475fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 22 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.248-2_254delAGGTGACAA	p.Gly83fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 6 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.1424-2_1430delAGGTGACAA	p.Gly475fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 22 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hematuria;C0033687:Proteinuria;C0423110:Downslanted palpebral fissures;C1408258:Kidney damage Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556411578; hg19: chrX-107838736;