chrX-108285009-A-G

Variant names:

• chrX-108285009-A-G
• rs963337
• NM_033641.4:c.144+25739T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033641.4(COL4A6):​c.144+25739T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 110,784 control chromosomes in the GnomAD database, including 3,217 homozygotes. There are 8,641 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (3217 hom., 8641 hem., cov: 23)
• Consequence: COL4A6 NM_033641.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.626
• Publications: 0 publications found

Genes affected

COL4A6 (HGNC:2208): (collagen type IV alpha 6 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. 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, alpha 5 type IV collagen, so that the gene pair shares a common promoter. Deletions in the alpha 5 gene that extend into the alpha 6 gene result in diffuse leiomyomatosis accompanying the X-linked Alport syndrome caused by the deletion in the alpha 5 gene. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]

COL4A6 Gene-Disease associations (from GenCC):

• hearing loss, X-linked 6

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, PanelApp Australia
• X-linked nonsyndromic hearing loss

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• premature ovarian failure 1

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4	c.144+25739T>C		intron_variant	Intron 3 of 44	ENST00000334504.12	NP_378667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A6	ENST00000334504.12	c.144+25739T>C		intron_variant	Intron 3 of 44	5	NM_033641.4	ENSP00000334733.7

Frequencies

GnomAD3 genomes AF: 0.264 AC: 29243 AN: 110726 Hom.: 3212 Cov.: 23

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.265

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

GnomAD4 genome AF: 0.264 AC: 29283 AN: 110784 Hom.: 3217 Cov.: 23 AF XY: 0.261 AC XY: 8641 AN XY: 33052

African (AFR) AF: 0.264 AC: 8047 AN: 30444

American (AMR) AF: 0.473 AC: 4902 AN: 10361

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 483 AN: 2635

East Asian (EAS) AF: 0.612 AC: 2118 AN: 3462

South Asian (SAS) AF: 0.415 AC: 1075 AN: 2589

European-Finnish (FIN) AF: 0.128 AC: 767 AN: 5991

Middle Eastern (MID) AF: 0.217 AC: 47 AN: 217

European-Non Finnish (NFE) AF: 0.212 AC: 11240 AN: 52894

Other (OTH) AF: 0.260 AC: 394 AN: 1515

Alfa AF: 0.246 Hom.: 7615

Bravo AF: 0.295

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.6
DANN	Benign	0.68
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs963337; hg19: chrX-107528239;