X-108692800-C-G

Variant names:

• chrX-108692800-C-G
• rs104886292
• NM_033380.3:c.4581C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_033380.3(COL4A5):​c.4581C>G​(p.Cys1527Trp) variant causes a missense change involving the alteration of a non-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. C1527S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.75
• Publications: 0 publications found

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]

COL4A5 Gene-Disease associations (from GenCC):

• Alport syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-108692798-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1908893.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant X-108692800-C-G is Pathogenic according to our data. Variant chrX-108692800-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3068581.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.4581C>G	p.Cys1527Trp	missense_variant	Exon 50 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.4581C>G	p.Cys1527Trp	missense_variant	Exon 50 of 53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Alport syndrome Pathogenic:1

Nov 05, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in COL4A5 is predicted to replace cysteine with tryptophan at codon 1527, p.(Cys1527Trp). The cysteine residue is highly conserved (100 vertebrates, UCSC), and is a critical residue involved in a disulphide bond in the NC1 domain (PMID: 9535854). There is a large physicochemical difference between cysteine and tryptophan. This variant is absent from the population database gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in any individuals with COL4A5-related disease in the relevant scientific literature. The variant alters COL4 trimer formation in an in vitro assay in HEK293 cells (PMID: 35243249). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.904). Another missense variant c.4561T>A, p.Cys1527Ser in the same codon (with a similar physicochemical difference) has been classified as likely pathogenic (PMID: 35789182). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PM5, PM2_Supporting, PS3_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;H
PhyloP100		1.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.95
MutPred		0.85		.;Loss of catalytic residue at M1519 (P = 0.0024);
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		0.018	Neutral
Varity_R		1.0
gMVP		0.99
Mutation Taster		=9/91	disease causing

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

Other links and lift over

dbSNP: rs104886292; hg19: chrX-107936030;