X-108156930-C-T

Variant names:

• chrX-108156930-C-T
• rs59121927
• NM_033641.4:c.*70G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033641.4(COL4A6):​c.*70G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,058,878 control chromosomes in the GnomAD database, including 714 homozygotes. There are 2,693 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (397 hom., 1452 hem., cov: 23)
  • Exomes 𝑓: 0.0055 (317 hom. 1241 hem.)
• Consequence: COL4A6 NM_033641.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.214
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-108156930-C-T is Benign according to our data. Variant chrX-108156930-C-T is described in ClinVar as Benign. ClinVar VariationId is 1270289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

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.*70G>A		3_prime_UTR	Exon 45 of 45	NP_378667.1	Q14031-2
	COL4A6	NM_001287758.2		c.*70G>A		3_prime_UTR	Exon 46 of 46	NP_001274687.1	A8MXH5
	COL4A6	NM_001847.4		c.*70G>A		3_prime_UTR	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.*70G>A		3_prime_UTR	Exon 45 of 45	ENSP00000334733.7	Q14031-2
	COL4A6	ENST00000372216.8	TSL:1	c.*70G>A		3_prime_UTR	Exon 45 of 45	ENSP00000361290.4	Q14031-1
	COL4A6	ENST00000621266.4	TSL:1	c.*70G>A		3_prime_UTR	Exon 44 of 44	ENSP00000482970.1	A0A087WZY5

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 5691 AN: 111338 Hom.: 400 Cov.: 23

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000770

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000660

Gnomad OTH AF: 0.0365

GnomAD4 exome AF: 0.00553 AC: 5242 AN: 947485 Hom.: 317 Cov.: 17 AF XY: 0.00463 AC XY: 1241 AN XY: 267799

African (AFR) AF: 0.184 AC: 4256 AN: 23184

American (AMR) AF: 0.0102 AC: 324 AN: 31714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16112

East Asian (EAS) AF: 0.00 AC: 0 AN: 29433

South Asian (SAS) AF: 0.000414 AC: 19 AN: 45873

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38957

Middle Eastern (MID) AF: 0.00706 AC: 20 AN: 2832

European-Non Finnish (NFE) AF: 0.000178 AC: 128 AN: 718639

Other (OTH) AF: 0.0121 AC: 495 AN: 40741

GnomAD4 genome AF: 0.0510 AC: 5686 AN: 111393 Hom.: 397 Cov.: 23 AF XY: 0.0432 AC XY: 1452 AN XY: 33593

African (AFR) AF: 0.176 AC: 5374 AN: 30473

American (AMR) AF: 0.0205 AC: 217 AN: 10576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3533

South Asian (SAS) AF: 0.000773 AC: 2 AN: 2588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6091

Middle Eastern (MID) AF: 0.0137 AC: 3 AN: 219

European-Non Finnish (NFE) AF: 0.000660 AC: 35 AN: 53056

Other (OTH) AF: 0.0361 AC: 55 AN: 1525

Alfa AF: 0.0424 Hom.: 155

Bravo AF: 0.0584

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.2
DANN	Benign	0.81
PhyloP100		-0.21
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: rs59121927; hg19: chrX-107400160; COSMIC: COSV57864735; COSMIC: COSV57864735;