X-108601467-G-A

Position:

• chrX-108601467-G-A

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.2023G>A​(p.Gly675Ser) 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: 21)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.88

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, 0.99
• PP5: Variant X-108601467-G-A is Pathogenic according to our data. Variant chrX-108601467-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1508138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108601467-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2023G>A	p.Gly675Ser	missense_variant	26/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2023G>A	p.Gly675Ser	missense_variant	26/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.847G>A	p.Gly283Ser	missense_variant	10/20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2023G>A	p.Gly675Ser	missense_variant	26/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	COL4A5: PM1:Strong, PM2, PM5, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 675 of the COL4A5 protein (p.Gly675Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome and/or COL4A5-related conditions (PMID: 15954103, 33040356, 36100708, 36588757). ClinVar contains an entry for this variant (Variation ID: 1508138). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. -

X-linked Alport syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 03, 2024

Variant summary: COL4A5 c.2023G>A (p.Gly675Ser) results in a non-conservative amino acid change located in the triple helical region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 179834 control chromosomes. c.2023G>A has been reported in the literature in individuals affected with Alport Syndrome, and Chronic Kidney Disease (examples: Nagel_2005, Boeckhaus_2020, Popp_2022, Demir_2022, Di_2022). These data indicate that the variant is likely to be associated with disease. Using a Split-Luciferase-Based trimer formation assay one publication reported experimental evidence that this variant disrupts normal function of the protein (example: Omachi_2018). The following publications have been ascertained in the context of this evaluation (PMID: 33040356, 36588757, 35020912, 15954103, 29526710, 36100708). ClinVar contains an entry for this variant (Variation ID: 1508138). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	.;D;D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;H;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.0	D;D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.98
MutPred		1.0		Gain of phosphorylation at G675 (P = 0.0056);Gain of phosphorylation at G675 (P = 0.0056);.;
MVP		1.0
MPC		0.30
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs104886157; hg19: chrX-107844697;