rs281874696

Positions:

• chrX-108615015-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_033380.3(COL4A5):​c.2500G>C​(p.Gly834Arg) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.58

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-108615015-G-C is Pathogenic according to our data. Variant chrX-108615015-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 24529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108615015-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2500G>C	p.Gly834Arg	missense_variant	30/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2500G>C	p.Gly834Arg	missense_variant	30/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1324G>C	p.Gly442Arg	missense_variant	14/20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2500G>C	p.Gly834Arg	missense_variant	30/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2019	Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (Stenson et al., 2014; Jais et al., 2000); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20378821) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 16, 2019	The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and not found in general population data. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 22, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 834 of the COL4A5 protein (p.Gly834Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 20378821; Invitae). ClinVar contains an entry for this variant (Variation ID: 24529). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL4A5 protein function. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. -

X-linked Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.6	H;H;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.1	D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.92
MutPred		1.0		Gain of methylation at G834 (P = 0.0435);Gain of methylation at G834 (P = 0.0435);.;
MVP		1.0
MPC		0.36
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs281874696; hg19: chrX-107858245;