rs104886306

Variant names:

• chrX-108696349-C-T
• rs104886306
• NM_033380.3:c.5047C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_033380.3(COL4A5):​c.5047C>T​(p.Arg1683*) variant causes a stop gained change. 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 (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.13

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00571 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108696349-C-T is Pathogenic according to our data. Variant chrX-108696349-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 24786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108696349-C-T is described in Lovd as [Pathogenic]. Variant chrX-108696349-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.5047C>T	p.Arg1683*	stop_gained	Exon 53 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.5047C>T	p.Arg1683*	stop_gained	Exon 53 of 53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked Alport syndrome Pathogenic:2

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, caused by missense variants mostly glycine substitutions that affect the conformation of the protein, and loss of function, caused by either protein truncating or missense variants, are known mechanisms of disease in this gene and are associated with Alport syndrome 1 (MIM#301050) (PMIDs: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant results in the truncation of part of the annotated C4 domain (NCBI). (I) 0704 - Another truncating variant comparable to the one identified in this case has limited previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Alport syndrome, end stage renal disease and hearing loss (ClinVar, LOVD, ARUP, PMID: 9848783, PMID: 10094548, PMID: 27627812). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant protein from transfected HEK293 cells demonstrated an inability to form complexes with alpha-3 or -4 chains (PMID: 18083113). (SP) 1205 - This variant has been shown to be maternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Feb 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1677*) in the COL4A5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the COL4A5 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 10094548, 12796257, 19728970, 19965530). ClinVar contains an entry for this variant (Variation ID: 24786). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.61
GERP RS		5.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs104886306; hg19: chrX-107939579;