rs104886167

Variant names:

• chrX-108601898-TC-T
• rs104886167
• NM_033380.3:c.2057delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033380.3(COL4A5):​c.2057delC​(p.Pro686GlnfsTer50) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: COL4A5 NM_033380.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.54
• Publications: 2 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108601898-TC-T is Pathogenic according to our data. Variant chrX-108601898-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 24482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2057delC	p.Pro686GlnfsTer50	frameshift_variant	Exon 27 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2057delC	p.Pro686GlnfsTer50	frameshift_variant	Exon 27 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.881delC	p.Pro294GlnfsTer50	frameshift_variant	Exon 11 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2057delC	p.Pro686GlnfsTer50	frameshift_variant	Exon 27 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1041803 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 327173

African (AFR) AF: 0.00 AC: 0 AN: 25074

American (AMR) AF: 0.00 AC: 0 AN: 29731

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18530

East Asian (EAS) AF: 0.00 AC: 0 AN: 28391

South Asian (SAS) AF: 0.00 AC: 0 AN: 50020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3951

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 803847

Other (OTH) AF: 0.00 AC: 0 AN: 43979

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 29, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17660027, 23371956, 32812400) -

May 24, 2022

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.Pro686Glnfs*50) in the COL4A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 24482). This premature translational stop signal has been observed in individual(s) with Alport syndrome (PMID: 17660027). This variant is not present in population databases (gnomAD no frequency). -

X-linked Alport syndrome Pathogenic:1

Feb 22, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs104886167; hg19: chrX-107845128;