rs867625069

Positions:

• chrX-108603054-G-A
• chrX-108603054-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The ENST00000328300.11(COL4A5):​c.2237G>A​(p.Gly746Glu) 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: 22)
• Consequence: COL4A5 ENST00000328300.11 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.17

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000328300.11
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-108603054-G-A is Pathogenic according to our data. Variant chrX-108603054-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 587146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108603054-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2237G>A	p.Gly746Glu	missense_variant	28/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2237G>A	p.Gly746Glu	missense_variant	28/53	1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000483338.1	c.1061G>A	p.Gly354Glu	missense_variant	12/20	1		ENSP00000495685
COL4A5	ENST00000361603.7	c.2237G>A	p.Gly746Glu	missense_variant	28/51	2		ENSP00000354505	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2020

For these reasons, this variant has been classified as Pathogenic. 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). This variant has been observed in individual(s) with Alport syndrome (PMID: 24033287, Invitae). ClinVar contains an entry for this variant (Variation ID: 587146). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 746 of the COL4A5 protein (p.Gly746Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

X-linked Alport syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Precision Medicine Center, Zhengzhou University

-

PM1:Located in a mutational hot spot PM2:not found in gnomAD 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.82
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	5.1	H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.2	D;D;.
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.99
MutPred		0.95		Gain of solvent accessibility (P = 0.0062);Gain of solvent accessibility (P = 0.0062);.;
MVP		1.0
MPC		0.39
ClinPred		1.0	D
GERP RS		5.7
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: rs867625069; hg19: chrX-107846284;