rs104886286

Variant names:

• chrX-108692924-C-T
• rs104886286
• NM_033380.3:c.4705C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_033380.3(COL4A5):​c.4705C>T​(p.Arg1569*) variant causes a stop gained, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000520870: "Additionally, functional studies have shown that R1569X prevents the expression of a3, a4, and a5 collagen chains (Kobayashi et al., 2008)."". Synonymous variant affecting the same amino acid position (i.e. R1569R) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.03664
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.04
• Publications: 8 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000520870: "Additionally, functional studies have shown that R1569X prevents the expression of a3, a4, and a5 collagen chains (Kobayashi et al., 2008)."
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108692924-C-T is Pathogenic according to our data. Variant chrX-108692924-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 24755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.4705C>T	p.Arg1569*	stop_gained splice_region	Exon 50 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.4687C>T	p.Arg1563*	stop_gained splice_region	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.4705C>T	p.Arg1569*	stop_gained splice_region	Exon 50 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.4699C>T	p.Arg1567*	stop_gained splice_region	Exon 48 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.4687C>T	p.Arg1563*	stop_gained splice_region	Exon 48 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000517 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		2.0
Vest4		0.97
GERP RS		4.0
PromoterAI		-0.0068	Neutral
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.037
dbscSNV1_RF	Benign	0.34
SpliceAI score (max)		0.18		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: rs104886286; hg19: chrX-107936154;