rs104886303

Variant names:

• chrX-108695409-T-G
• rs104886303
• NM_033380.3:c.4964T>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_033380.3(COL4A5):​c.4964T>G​(p.Leu1655Arg) 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 (★★). ClinVar reports functional evidence for this variant: "SCV001156656: "In vitro analysis of the variant protein demonstrates defective trimerization, leading to secretion of a less stable monomeric alpha chain (Kobayashi 2008)."" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1655L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 8.02
• Publications: 14 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 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001156656: "In vitro analysis of the variant protein demonstrates defective trimerization, leading to secretion of a less stable monomeric alpha chain (Kobayashi 2008)."; SCV000612998: Assessment of experimental evidence suggests this variant results in abnormal protein function. Introduction of this variant into the mouse homologue resulted in defective formation of the collagen heterotrimer (PMID: 18083113).; SCV000965555: Experimental studies have shown that this missense change affects COL4A5 function (PMID: 18083113).
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.992
• PP5: Variant X-108695409-T-G is Pathogenic according to our data. Variant chrX-108695409-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 10466.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.4964T>G	p.Leu1655Arg	missense	Exon 52 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.4946T>G	p.Leu1649Arg	missense	Exon 50 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.4964T>G	p.Leu1655Arg	missense	Exon 52 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.4958T>G	p.Leu1653Arg	missense	Exon 50 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.4946T>G	p.Leu1649Arg	missense	Exon 50 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00000721 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
4	-	-	X-linked Alport syndrome (5)
1	-	-	Alport syndrome (1)
1	-	-	COL4A5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.94		Loss of stability (P = 0.0081)
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		1.0
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104886303; hg19: chrX-107938639;