rs281874760

Variant names:

• chrX-108440186-GGGCAGCCTGCAGA-G
• rs281874760
• NM_033380.3:c.65_77delAGCCTGCAGAGGC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_033380.3(COL4A5):​c.65_77delAGCCTGCAGAGGC​(p.Gln22LeufsTer18) variant causes a frameshift change. 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q22Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 20)
• Consequence: COL4A5 NM_033380.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.18
• 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 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1107 pathogenic variants in the truncated region.
• PP5: Variant X-108440186-GGGCAGCCTGCAGA-G is Pathogenic according to our data. Variant chrX-108440186-GGGCAGCCTGCAGA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 24229.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.65_77delAGCCTGCAGAGGC	p.Gln22LeufsTer18	frameshift	Exon 1 of 53	NP_203699.1
	COL4A5	NM_000495.5		c.65_77delAGCCTGCAGAGGC	p.Gln22LeufsTer18	frameshift	Exon 1 of 51	NP_000486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.65_77delAGCCTGCAGAGGC	p.Gln22LeufsTer18	frameshift	Exon 1 of 53	ENSP00000331902.7
	COL4A5	ENST00000477429.1	TSL:1	n.347_359delAGCCTGCAGAGGC		non_coding_transcript_exon	Exon 1 of 2
	COL4A5	ENST00000361603.7	TSL:2	c.65_77delAGCCTGCAGAGGC	p.Gln22LeufsTer18	frameshift	Exon 1 of 51	ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 20

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

GnomAD4 genome Cov.: 20

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs281874760; hg19: chrX-107683416;