rs397515495

Variant names:

• chrX-108614949-CCTCCTGG-AACCTGGACCAATGGGACCAATGGGAACAC
• rs397515495
• NM_033380.3:c.2434_2441delCCTCCTGGinsAACCTGGACCAATGGGACCAATGGGAACAC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP2

The NM_033380.3(COL4A5):​c.2434_2441delCCTCCTGGinsAACCTGGACCAATGGGACCAATGGGAACAC​(p.Pro812AsnfsTer50) variant causes a frameshift, missense change. 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 frameshift, missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.78
• Publications: 1 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: G2P, ClinGen
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Myriad Women’s Health

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.2434_2441delCCTCCTGGinsAACCTGGACCAATGGGACCAATGGGAACAC	p.Pro812AsnfsTer50	frameshift missense	Exon 30 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.2434_2441delCCTCCTGGinsAACCTGGACCAATGGGACCAATGGGAACAC	p.Pro812AsnfsTer50	frameshift missense	Exon 30 of 51	NP_000486.1	P29400-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.2434_2441delCCTCCTGGinsAACCTGGACCAATGGGACCAATGGGAACAC	p.Pro812AsnfsTer50	frameshift missense	Exon 30 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000483338.1	TSL:1	c.1258_1265delCCTCCTGGinsAACCTGGACCAATGGGACCAATGGGAACAC	p.Pro420AsnfsTer50	frameshift missense	Exon 14 of 20	ENSP00000495685.1	Q49AM6
	COL4A5	ENST00000949143.1		c.2434_2441delCCTCCTGGinsAACCTGGACCAATGGGACCAATGGGAACAC	p.Pro812AsnfsTer50	frameshift missense	Exon 30 of 51	ENSP00000619202.1

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8

Splicing

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

Other links and lift over

dbSNP: rs397515495; hg19: chrX-107858179;