rs104886292

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-108692800-C-G
• chrX-108692800-C-A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV004812425: The variant alters COL4 trimer formation in an in vitro assay in HEK293 cells (PMID:35243249).". 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: G2P, ClinGen
• X-linked Alport syndrome

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004812425: The variant alters COL4 trimer formation in an in vitro assay in HEK293 cells (PMID: 35243249).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.4581C>G	p.Cys1527Trp	missense	Exon 50 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.4563C>G	p.Cys1521Trp	missense	Exon 48 of 51	NP_000486.1	P29400-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.4581C>G	p.Cys1527Trp	missense	Exon 50 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.4575C>G	p.Cys1525Trp	missense	Exon 48 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.4563C>G	p.Cys1521Trp	missense	Exon 48 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	X-linked Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		1.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	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;