rs104886388

Positions:

• chrX-108666487-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_033380.3(COL4A5):​c.3455-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9483
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.03

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• PP5: Variant X-108666487-A-G is Pathogenic according to our data. Variant chrX-108666487-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 24633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108666487-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.3455-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.3455-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000361603.7	c.3455-9A>G		splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000354505	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

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

Jan 15, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 10862091). This variant has been observed in individual(s) with clinical features of Alport syndrome (PMID: 10862091, Invitae). This variant is also known as 3657-9A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 24633). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 38 of the COL4A5 gene. It does not directly change the encoded amino acid sequence of the COL4A5 protein. -

X-linked Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The COL4A5 c.3455-9A>G variant has been reported in hemizygous state in individuals affected with Alport syndrome (Martin P et al.). Experimental studies have shown that this variant disrupts mRNA splicing (Martin P et al). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This sequence change falls in intron 38 of the COL4A5 gene. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Pathogenic	30
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs104886388; hg19: chrX-107909717;