X-108598793-G-T

Variant names:

• chrX-108598793-G-T
• rs104886142
• NM_033380.3:c.1871G>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_033380.3(COL4A5):​c.1871G>T​(p.Gly624Val) 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:3
• Conservation: PhyloP100: 9.31

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.

• PM1: In a compositionally_biased_region Pro residues (size 22) in uniprot entity CO4A5_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant X-108598793-G-T is Pathogenic according to our data. Variant chrX-108598793-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1077043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1871G>T	p.Gly624Val	missense_variant	Exon 25 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1871G>T	p.Gly624Val	missense_variant	Exon 25 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.695G>T	p.Gly232Val	missense_variant	Exon 9 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.1871G>T	p.Gly624Val	missense_variant	Exon 25 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 24, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.Gly624 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24470729, 26934356, 21332469, 26809805, 17396119, 29854973). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not been reported in the literature in individuals with COL4A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1077043). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 624 of the COL4A5 protein (p.Gly624Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. -

X-linked Alport syndrome Pathogenic:1

-

Precision Medicine Center, Zhengzhou University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM1:Located in a mutational hot spot PM2:not found in gnomAD PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before PP2:Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;D;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.2	D;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0090	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0, 1.0	.;D;D
Vest4		0.93
MutPred		0.58		Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);.;
MVP		0.96
MPC		0.37
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: 15

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

Publications

LitVar

Other links and lift over

dbSNP: rs104886142; hg19: chrX-107842023;