rs1556453276

Variant names:

• chrX-108680927-AG-A
• rs1556453276
• NM_033380.3:c.4063delG

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.4063delG​(p.Glu1355AsnfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E1355E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.123
• 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: 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-108680927-AG-A is Pathogenic according to our data. Variant chrX-108680927-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 447210.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.4063delG	p.Glu1355AsnfsTer22	frameshift_variant	Exon 46 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.4063delG	p.Glu1355AsnfsTer22	frameshift_variant	Exon 46 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000361603.7	c.4045delG	p.Glu1349AsnfsTer22	frameshift_variant	Exon 44 of 51	2		ENSP00000354505.2
COL4A5	ENST00000489230.1	n.466delG		non_coding_transcript_exon_variant	Exon 5 of 8	5
COL4A5	ENST00000510690.2	n.557delG		non_coding_transcript_exon_variant	Exon 4 of 11	4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Aug 31, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). This variant has not been reported in the literature in individuals with COL4A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 447210). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu1349Asnfs*22) in the COL4A5 gene. It is expected to result in an absent or disrupted protein product. -

Apr 26, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked Alport syndrome Pathogenic:2

Aug 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 06, 2021

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.12
Mutation Taster		=1/199	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: rs1556453276; hg19: chrX-107924157;