rs1556421106

Variant names:

• chrX-108624275-TGCCTGGAGACCCAGGGCA-T
• rs1556421106
• NM_033380.3:c.2958_2975delGCCTGGAGACCCAGGGCA

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.2958_2975delGCCTGGAGACCCAGGGCA​(p.Pro987_Gln992del) 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: 23)
• Consequence: COL4A5 NM_033380.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.20

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-108624275-TGCCTGGAGACCCAGGGCA-T is Pathogenic according to our data. Variant chrX-108624275-TGCCTGGAGACCCAGGGCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520604.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.2958_2975delGCCTGGAGACCCAGGGCA	p.Pro987_Gln992del	disruptive_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.2958_2975delGCCTGGAGACCCAGGGCA	p.Pro987_Gln992del	disruptive_inframe_deletion	Exon 34 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1782_1799delGCCTGGAGACCCAGGGCA	p.Pro595_Gln600del	disruptive_inframe_deletion	Exon 18 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2958_2975delGCCTGGAGACCCAGGGCA	p.Pro987_Gln992del	disruptive_inframe_deletion	Exon 34 of 51	2		ENSP00000354505.2
COL4A5	ENST00000505728.1	c.189_206delGCCTGGAGACCCAGGGCA	p.Pro64_Gln69del	disruptive_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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 04, 2021

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: 520604). 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.2958_2975del, 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, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of six amino acids within the triple helical domain expected to disrupt normal protein folding and function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with Alport syndrome to our knowledge; This variant is associated with the following publications: (PMID: 28330790) -

Inborn genetic diseases Pathogenic:1

Dec 26, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs1556421106; hg19: chrX-107867505;