rs104886372

Positions:

• chrX-108624235-G-A
• chrX-108624235-G-T

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.2918-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: COL4A5 NM_033380.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.90

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 0.01930654 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108624235-G-A is Pathogenic according to our data. Variant chrX-108624235-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 587182.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108624235-G-A is described in Lovd as [Pathogenic]. Variant chrX-108624235-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2918-1G>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.2918-1G>A		splice_acceptor_variant		1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000483338.1	c.1742-1G>A		splice_acceptor_variant		1		ENSP00000495685
COL4A5	ENST00000361603.7	c.2918-1G>A		splice_acceptor_variant		2		ENSP00000354505	P1
COL4A5	ENST00000505728.1	c.151-1G>A		splice_acceptor_variant		3		ENSP00000424137

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Alport syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 31, 2019	A hemizygous 3' splice site variation in intron 33 of the COL4A5 gene that affects the invariant AG acceptor splice site of exon 34 was detected. The observed variant c.2918-1G>A (3' splice site) has previously been reported in patients affected with Alport syndrome (Moriniere et al 2014). The variant has not been reported in the 1000 Genomes and ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference base is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Mar 11, 2020	A heterozygous splice site variation in intron 33 of the COL4A5 gene was detected. The observed variant c.c.2918-1G>A has not been reported in the 1000 genomes and ExAC databases. It is reported in patient affected with Alport syndrome by Moriniere et al. 2014. The in silico prediction of the variant is damaging by MutationTaster2. In summary, the variant meets our criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: 2
DS_AL_spliceai		1.0		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: rs104886372; hg19: chrX-107867465;