rs104886374

Variant names:

• chrX-108624276-GCCTGGAGACCCAGGGCAA-G
• rs104886374
• NM_033380.3:c.2965_2982delGACCCAGGGCAACCTGGA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM4 PP3 PP5_Very_Strong

The NM_033380.3(COL4A5):​c.2965_2982delGACCCAGGGCAACCTGGA​(p.Asp989_Gly994del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.20
• 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 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_033380.3
• 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-108624276-GCCTGGAGACCCAGGGCAA-G is Pathogenic according to our data. Variant chrX-108624276-GCCTGGAGACCCAGGGCAA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 24580.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.2965_2982delGACCCAGGGCAACCTGGA	p.Asp989_Gly994del	conservative_inframe_deletion	Exon 34 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2965_2982delGACCCAGGGCAACCTGGA	p.Asp989_Gly994del	conservative_inframe_deletion	Exon 34 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1789_1806delGACCCAGGGCAACCTGGA	p.Asp597_Gly602del	conservative_inframe_deletion	Exon 18 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2965_2982delGACCCAGGGCAACCTGGA	p.Asp989_Gly994del	conservative_inframe_deletion	Exon 34 of 51	2		ENSP00000354505.2
COL4A5	ENST00000505728.1	c.196_213delGACCCAGGGCAACCTGGA	p.Asp66_Gly71del	conservative_inframe_deletion	Exon 2 of 5	3		ENSP00000424137.1

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Oct 10, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 24580). This variant is also known as 3161-3178del del987-992. This variant has been observed in individuals with clinical features of Alport syndrome (PMID: 10094548; Invitae). This variant is not present in population databases (ExAC no frequency). This variant, c.2965_2982del, results in the deletion of 6 amino acid(s) of the COL4A5 protein (p.Asp989_Gly994del), but otherwise preserves the integrity of the reading frame. -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL4A5: PM1:Strong, PM2, PM4, PS4:Moderate, PP4 -

X-linked Alport syndrome Pathogenic:2

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2019

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp989_Gly994del variant in the COL4A5 gene is a hemizygous in-frame deletion variant, which results in the removal of six amino acids in coding exon 34 of the COL4A5 gene (51 coding exons in total; NP_000486.1) and maps to the triple-helical region of the protein. This variant has not been observed in the Genome Aggregation Database (gnomAD), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in in a hemizygous male with end stage renal failure, characteristic basement membrane changes and a positive family history (PMID: 10094548). In ClinVar, this in-frame deletion overlaps with multiple Pathogenic/ Likely Pathogenic variants. Based on the evidence presented, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs104886374; hg19: chrX-107867506;