rs753437190

Positions:

• chrX-108591560-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_033380.3(COL4A5):​c.1340-1G>A variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 splice_acceptor
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.71

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.016351458 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.4, offset of 1, new splice context is: ctttctttatcttactcaAGtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108591560-G-A is Pathogenic according to our data. Variant chrX-108591560-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 585537.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1340-1G>A		splice_acceptor_variant		ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1340-1G>A		splice_acceptor_variant		1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000483338.1	c.164-1G>A		splice_acceptor_variant		1		ENSP00000495685
COL4A5	ENST00000361603.7	c.1340-1G>A		splice_acceptor_variant		2		ENSP00000354505	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183216 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	33
DANN	Benign	0.85
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: 2
DS_AL_spliceai		0.99		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: rs753437190; hg19: chrX-107834790;