chrX-108157190-C-T

Variant names:

• chrX-108157190-C-T
• rs1302611212
• NM_033641.4:c.4883G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_033641.4(COL4A6):​c.4883G>A​(p.Arg1628Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000107 in 1,210,250 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000091 (0 hom. 2 hem.)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05
• 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), Ambry Genetics, ClinGen
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033641.4. 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
	COL4A6	NM_033641.4	MANE Select	c.4883G>A	p.Arg1628Gln	missense	Exon 45 of 45	NP_378667.1	Q14031-2
	COL4A6	NM_001287758.2		c.4934G>A	p.Arg1645Gln	missense	Exon 46 of 46	NP_001274687.1	A8MXH5
	COL4A6	NM_001847.4		c.4886G>A	p.Arg1629Gln	missense	Exon 45 of 45	NP_001838.2	Q14031-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A6	ENST00000334504.12	TSL:5 MANE Select	c.4883G>A	p.Arg1628Gln	missense	Exon 45 of 45	ENSP00000334733.7	Q14031-2
	COL4A6	ENST00000372216.8	TSL:1	c.4886G>A	p.Arg1629Gln	missense	Exon 45 of 45	ENSP00000361290.4	Q14031-1
	COL4A6	ENST00000621266.4	TSL:1	c.4811G>A	p.Arg1604Gln	missense	Exon 44 of 44	ENSP00000482970.1	A0A087WZY5

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112057 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1098193 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363551

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54148

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 842102

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112057 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34227

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

African (AFR) AF: 0.00 AC: 0 AN: 30834

American (AMR) AF: 0.00 AC: 0 AN: 10601

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6165

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53145

Other (OTH) AF: 0.00 AC: 0 AN: 1503

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.65
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.018	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.67		Loss of methylation at R1629 (P = 0.0238)
MVP		0.99
MPC		0.22
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.54
gMVP		0.83
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1302611212; hg19: chrX-107400420; COSMIC: COSV100564777; COSMIC: COSV100564777;