rs397515497

Positions:

• chrX-108626206-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_033380.3(COL4A5):​c.3107-4A>G variant causes a splice region, 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. 3/3 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_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9948
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.35

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-108626206-A-G is Pathogenic according to our data. Variant chrX-108626206-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1465065.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.3107-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.3107-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_033380.3
COL4A5	ENST00000483338.1	c.1931-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
COL4A5	ENST00000361603.7	c.3107-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		P1
COL4A5	ENST00000505728.1	c.340-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00304 Hom.: 0

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

Invitae

Apr 09, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant is associated with the activation of a cryptic splice site in intron 35 (PMID: 21505094). This variant has been observed in individual(s) with clinical features of Alport syndrome (PMID: 29959198, 21505094). ClinVar contains an entry for this variant (Variation ID: 38773). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 35 of the COL4A5 gene. It does not directly change the encoded amino acid sequence of the COL4A5 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of one amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_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: rs397515497; hg19: chrX-107869436;