X-108622826-G-C

Position:

• chrX-108622826-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The ENST00000328300.11(COL4A5):​c.2917+1G>C variant causes a splice donor 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: 23)
• Consequence: COL4A5 ENST00000328300.11 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.47

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: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.029353822 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-108622826-G-C is Pathogenic according to our data. Variant chrX-108622826-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 24574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108622826-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2917+1G>C		splice_donor_variant		ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2917+1G>C		splice_donor_variant		1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000483338.1	c.1741+1G>C		splice_donor_variant		1		ENSP00000495685
COL4A5	ENST00000361603.7	c.2917+1G>C		splice_donor_variant		2		ENSP00000354505	P1
COL4A5	ENST00000505728.1	c.150+1G>C		splice_donor_variant		3		ENSP00000424137

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 28, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 32659759). ClinVar contains an entry for this variant (Variation ID: 24574). This variant is also known as c.3119+1G>C. Disruption of this splice site has been observed in individuals with Alport syndrome (PMID: 8940267, 32659759). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 33 of the COL4A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

X-linked Alport syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 23, 2022	Variant summary: COL4A5 c.2917+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Lv_2020). The variant was absent in 180606 control chromosomes. c.2917+1G>C has been reported in the literature as a hemizygous genotype in two patients affected with Alport Syndrome 1, X-Linked Recessive (Knebelman_1996, Groopman_2019) and as a heterozygous genotype in 2 females (proband and mother) with Hematuria, a related phenotype (Lv_2020). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	in vitro	Institute of Clinical Laboratory Science, Nanjing University Affiliated Jinling Hospital	May 21, 2017	A heterozygous variant c.2767g > t (p.gly923cys) was found in exon 32 of COL4A5 gene in the proband, which is a new variant. Sanger sequencing confirmed that the mutation was co isolated from the disease in the family. In vitro minigene experiment showed that the mutation of c.2767g > t could cause 96 bases missing in exon 33 of COL4A5 gene -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.56		Position offset: 3
DS_DL_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: rs104886371; hg19: chrX-107866056;