rs104886356

Variant names:

• chrX-108614978-GGGACCACCA-G
• rs104886356
• NM_033380.3:c.2475_2483delACCACCAGG

Your query was ambiguous. Multiple possible variants found:

• chrX-108614978-GGGACCACCA-G
• chrX-108614978-GGGACCACCA-GGGACCACCAGGACCACCA

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM4 PP3 PP5_Very_Strong

The NM_033380.3(COL4A5):​c.2475_2483delACCACCAGG​(p.Pro826_Gly828del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 8.29

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_033380.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-108614978-GGGACCACCA-G is Pathogenic according to our data. Variant chrX-108614978-GGGACCACCA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108614978-GGGACCACCA-G is described in Lovd as [Pathogenic]. Variant chrX-108614978-GGGACCACCA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2475_2483delACCACCAGG	p.Pro826_Gly828del	disruptive_inframe_deletion	Exon 30 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2475_2483delACCACCAGG	p.Pro826_Gly828del	disruptive_inframe_deletion	Exon 30 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1299_1307delACCACCAGG	p.Pro434_Gly436del	disruptive_inframe_deletion	Exon 14 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2475_2483delACCACCAGG	p.Pro826_Gly828del	disruptive_inframe_deletion	Exon 30 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jul 16, 2023

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. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). ClinVar contains an entry for this variant (Variation ID: 24527). This variant is also known as 822delGPP. This variant has been observed in individuals with clinical features of Alport syndrome (PMID: 10094548, 31937884; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.2475_2483del, results in the deletion of 3 amino acid(s) of the COL4A5 protein (p.Pro826_Gly828del), but otherwise preserves the integrity of the reading frame. -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL4A5: PM2, PM4, PS4:Moderate, PP4 -

Jun 04, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and not found in general population data. -

X-linked Alport syndrome Pathogenic:1 Other:1

Jan 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 11-22-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104886356; hg19: chrX-107858208;