X-108586590-AT-ATTT

Variant names:

• chrX-108586590-A-ATT
• rs104886089
• NM_033380.3:c.1033-16_1033-15dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033380.3(COL4A5):​c.1033-16_1033-15dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000101 in 992,465 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000010 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.409
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1033-16_1033-15dupTT		intron_variant	Intron 18 of 52	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1033-25_1033-24insTT		intron_variant	Intron 18 of 52	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.-144-25_-144-24insTT		intron_variant	Intron 2 of 19	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.1033-25_1033-24insTT		intron_variant	Intron 18 of 50	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000101 AC: 1 AN: 992465 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 318705

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23578

American (AMR) AF: 0.00 AC: 0 AN: 32222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17419

East Asian (EAS) AF: 0.00 AC: 0 AN: 27542

South Asian (SAS) AF: 0.00 AC: 0 AN: 48487

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37799

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3733

European-Non Finnish (NFE) AF: 0.00000132 AC: 1 AN: 760167

Other (OTH) AF: 0.00 AC: 0 AN: 41518

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.41
La Branchor		0.71
BranchPoint Hunter		6.0

Splicing

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

Other links and lift over

dbSNP: rs104886089; hg19: chrX-107829820;