rs281874736

Variant names:

• chrX-108687498-T-TGGTCCCCCTGGTCCAGATGGATTGCAAGGTCCCCCA
• rs281874736
• NM_033380.3:c.4344_4379dupTCCAGATGGATTGCAAGGTCCCCCAGGTCCCCCTGG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM4 PP3

The NM_033380.3(COL4A5):​c.4344_4379dupTCCAGATGGATTGCAAGGTCCCCCAGGTCCCCCTGG​(p.Gly1460_Thr1461insProAspGlyLeuGlnGlyProProGlyProProGly) variant causes a disruptive inframe insertion 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 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.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.15
• 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: 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.4344_4379dupTCCAGATGGATTGCAAGGTCCCCCAGGTCCCCCTGG	p.Gly1460_Thr1461insProAspGlyLeuGlnGlyProProGlyProProGly	disruptive_inframe_insertion	Exon 49 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.4344_4379dupTCCAGATGGATTGCAAGGTCCCCCAGGTCCCCCTGG	p.Gly1460_Thr1461insProAspGlyLeuGlnGlyProProGlyProProGly	disruptive_inframe_insertion	Exon 49 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000361603.7	c.4326_4361dupTCCAGATGGATTGCAAGGTCCCCCAGGTCCCCCTGG	p.Gly1454_Thr1455insProAspGlyLeuGlnGlyProProGlyProProGly	disruptive_inframe_insertion	Exon 47 of 51	2		ENSP00000354505.2
COL4A5	ENST00000515658.1	c.138_173dupTCCAGATGGATTGCAAGGTCCCCCAGGTCCCCCTGG	p.Gly58_Thr59insProAspGlyLeuGlnGlyProProGlyProProGly	disruptive_inframe_insertion	Exon 3 of 4	5		ENSP00000423520.1
COL4A5	ENST00000510690.2	n.838_873dupTCCAGATGGATTGCAAGGTCCCCCAGGTCCCCCTGG		non_coding_transcript_exon_variant	Exon 7 of 11	4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1
Mutation Taster		=50/50	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs281874736; hg19: chrX-107930728;