rs104886225

Positions:

• chrX-108655403-G-A
• chrX-108655403-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.3319G>A​(p.Gly1107Arg) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.31

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-108655403-G-A is Pathogenic according to our data. Variant chrX-108655403-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 24617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108655403-G-A is described in Lovd as [Pathogenic]. Variant chrX-108655403-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.3319G>A	p.Gly1107Arg	missense_variant	37/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.3319G>A	p.Gly1107Arg	missense_variant	37/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000361603.7	c.3319G>A	p.Gly1107Arg	missense_variant	37/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked Alport syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 17, 2022	ACMG classification criteria: PS4 strong, PM1, PM2 moderated, PP1 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 20, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with X-linked Alport syndrome 1 (MIM#301050). Dominant negative is caused mostly by glycine substitutions that affect the conformation of the protein, and loss of function can be caused by either protein truncating or missense variants (PMID: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. Males are typically more severely affected than females (PMID: 19965530). (I) 0115 - Variants in this gene are known to have variable expressivity. There is intrafamilial variability among affected carrier females, possibly due to variable X-inactivation (PMID: 14514738). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional glycine change within a Gly-X-Y motif (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Gly1107Glu)) has been reported once as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and observed in a family with Alport syndrome (PMID: 34225668, ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	GenePathDx, GenePath diagnostics	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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); This variant is associated with the following publications: (PMID: 10094548, 10561141, 30808327, 30577881, 29526710, 26809805, 29098738, 34225668, 31328266, 10752524, 24077912) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 03, 2021	This sequence change replaces glycine with arginine at codon 1107 of the COL4A5 protein (p.Gly1107Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 X-linked Alport syndrome (PMID: 10094548, 29098738). ClinVar contains an entry for this variant (Variation ID: 24617). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.80
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.9	H;H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		1.0
MutPred		0.99		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);
MVP		1.0
MPC		0.36
ClinPred		1.0	D
GERP RS		5.5
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: rs104886225; hg19: chrX-107898633; COSMIC: COSV60359152;