rs104886251

Positions:

• chrX-108668373-G-A
• chrX-108668373-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000328300.11(COL4A5):​c.3659G>A​(p.Gly1220Asp) 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. G1220V) has been classified 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:4
• Conservation: PhyloP100: 9.46

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 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000328300.11
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-108668373-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 453113.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-108668373-G-A is Pathogenic according to our data. Variant chrX-108668373-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108668373-G-A is described in Lovd as [Pathogenic]. Variant chrX-108668373-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.3659G>A	p.Gly1220Asp	missense_variant	41/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.3659G>A	p.Gly1220Asp	missense_variant	41/53	1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000361603.7	c.3659G>A	p.Gly1220Asp	missense_variant	41/51	2		ENSP00000354505	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked Alport syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	INGEBI, INGEBI / CONICET	Jul 15, 2021	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.3659 G>A (p.Gly1220Asp) in COL4A5 gene is absent from population databases, so PM2 applied. This variant impacts a glycine residue in the Gly-X-Y motifs of the collagene gene which are criticial for triple helical structure formation meeting PM1 rule. Computational evidence predicted a damage impact of the mutation to the protein (PP3; REVEL:0.98). G1220D variant has been found twice in Alport Syndromes's patients (PMID: 10094548 and this report), applying to PP4 and PS4_Sup. Considering the infromation: PM2, PM1, PP3, PP4 and Ps4_Sup the variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Precision Medicine Center, Zhengzhou University	-	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 -
Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 30, 2021

For these reasons, this variant has been classified as 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 Alport syndrome (PMID: 22921432, 33532864, 10094548). ClinVar contains an entry for this variant (Variation ID: 24666). This variant is also known as c.3861G>A. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 1220 of the COL4A5 protein (p.Gly1220Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.97		Loss of methylation at K1222 (P = 0.0832);Loss of methylation at K1222 (P = 0.0832);
MVP		1.0
MPC		0.39
ClinPred		1.0	D
GERP RS		6.0
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: rs104886251; hg19: chrX-107911603;