chrX-108620409-G-T

Position:

• chrX-108620409-G-T

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.2660G>T​(p.Gly887Val) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.57

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, 0.994
• PP5: Variant X-108620409-G-T is Pathogenic according to our data. Variant chrX-108620409-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1508191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108620409-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2660G>T	p.Gly887Val	missense_variant	31/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2660G>T	p.Gly887Val	missense_variant	31/53	1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000483338.1	c.1484G>T	p.Gly495Val	missense_variant	15/20	1		ENSP00000495685
COL4A5	ENST00000361603.7	c.2660G>T	p.Gly887Val	missense_variant	31/51	2		ENSP00000354505	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 26, 2020	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. 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). 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 has been observed in individual(s) with clinical features of Alport syndrome (PMID: 15954103, Invitae). ClinVar contains an entry for this variant (Variation ID: 24549). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 887 of the COL4A5 protein (p.Gly887Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant disrupts the p.Gly887 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 20378821), which suggests that this may be a clinically significant amino acid residue. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2023	Reported in a patient with Alport syndrome in published literature (Nagel et al., 2005); clinical information was not provided; Not observed at significant frequency in large population cohorts (gnomAD); 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 (HGMD; Jais et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15954103, 24077912, 10752524) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.8	H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.8	D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	.;D;D
Vest4		1.0
MutPred		0.99		Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);.;
MVP		0.99
MPC		0.37
ClinPred		1.0	D
GERP RS		6.2
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: rs104886201; hg19: chrX-107863639;