rs281874702

chrX-108621821-G-AchrX-108621821-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_033380.3(COL4A5):c.2696G>A(p.Gly899Asp) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G899S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.20

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-108621820-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522481.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-108621821-G-A is Pathogenic according to our data. Variant chrX-108621821-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108621821-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.2696G>A	p.Gly899Asp	missense_variant	32/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.2696G>A	p.Gly899Asp	missense_variant	32/53	1	NM_033380.3
COL4A5	ENST00000483338.1	c.1520G>A	p.Gly507Asp	missense_variant	16/20	1
COL4A5	ENST00000361603.7	c.2696G>A	p.Gly899Asp	missense_variant	32/51	2		P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 14, 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. This variant disrupts the p.Gly899 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 21505094), which suggests that this may be a clinically significant amino acid residue. 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 sequence change replaces glycine with aspartic acid at codon 899 of the COL4A5 protein (p.Gly899Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. ClinVar contains an entry for this variant (Variation ID: 439521). This missense change has been observed in individual(s) with clinical features of Alport syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 11, 2017	The COL4A5 c.2696G>A, p.Gly899Asp variant has not been reported in the medical literature, listed in gene-specific variant databases or the ClinVar database, nor observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). However, another missense at this residue (p.Gly899Val) has been implicated in Alport syndrome (Ma 2011). The glycine at residue 899 is highly conserved, and lies in the collagen triple-helix repeat domain. Computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as likely pathogenic. References: Ma J et al. Twenty-one novel mutations identified in the COL4A5 gene in Chinese patients with X-linked Alport's syndrome confirmed by skin biopsy. Nephrol Dial Transplant. 2011 26(12):4003-10. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 25, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
Cadd	Uncertain	25
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.3	D;D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		1.0
MutPred		0.99		Gain of glycosylation at T894 (P = 0.1309);Gain of glycosylation at T894 (P = 0.1309);.;
MVP		1.0
MPC		0.39
ClinPred		1.0	D
GERP RS		5.7
Varity_R		1.0
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: rs281874702; hg19: chrX-107865051;