rs769785668

Variant names:

• chrX-108160449-G-C
• rs769785668
• NM_033641.4:c.4525+14C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_033641.4(COL4A6):​c.4525+14C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,182,847 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 56 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.00015 (0 hom. 53 hem.)
• Consequence: COL4A6 NM_033641.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.19
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-108160449-G-C is Benign according to our data. Variant chrX-108160449-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 258279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 3 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.4525+14C>G		intron	N/A	NP_378667.1	Q14031-2
	COL4A6	NM_001287758.2		c.4576+14C>G		intron	N/A	NP_001274687.1	A8MXH5
	COL4A6	NM_001847.4		c.4528+14C>G		intron	N/A	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.4525+14C>G		intron	N/A	ENSP00000334733.7	Q14031-2
	COL4A6	ENST00000372216.8	TSL:1	c.4528+14C>G		intron	N/A	ENSP00000361290.4	Q14031-1
	COL4A6	ENST00000621266.4	TSL:1	c.4453+14C>G		intron	N/A	ENSP00000482970.1	A0A087WZY5

Frequencies

GnomAD3 genomes AF: 0.0000624 AC: 7 AN: 112218 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.0000940

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000910 AC: 14 AN: 153926 AF XY: 0.000132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000786

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000862

Gnomad OTH exome AF: 0.000270

GnomAD4 exome AF: 0.000154 AC: 165 AN: 1070575 Hom.: 0 Cov.: 30 AF XY: 0.000154 AC XY: 53 AN XY: 344373

African (AFR) AF: 0.000271 AC: 7 AN: 25785

American (AMR) AF: 0.0000617 AC: 2 AN: 32421

Ashkenazi Jewish (ASJ) AF: 0.000742 AC: 13 AN: 17531

East Asian (EAS) AF: 0.00 AC: 0 AN: 29734

South Asian (SAS) AF: 0.000102 AC: 5 AN: 49049

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39633

Middle Eastern (MID) AF: 0.00850 AC: 34 AN: 4001

European-Non Finnish (NFE) AF: 0.000116 AC: 96 AN: 827499

Other (OTH) AF: 0.000178 AC: 8 AN: 44922

GnomAD4 genome AF: 0.0000623 AC: 7 AN: 112272 Hom.: 0 Cov.: 24 AF XY: 0.0000871 AC XY: 3 AN XY: 34426

African (AFR) AF: 0.00 AC: 0 AN: 30887

American (AMR) AF: 0.00 AC: 0 AN: 10642

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3562

South Asian (SAS) AF: 0.00 AC: 0 AN: 2679

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6205

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.0000940 AC: 5 AN: 53207

Other (OTH) AF: 0.00 AC: 0 AN: 1532

Alfa AF: 0.000435 Hom.: 2

Bravo AF: 0.0000718

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.9
DANN	Benign	0.60
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

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: rs769785668; hg19: chrX-107403679;