rs201589060

Variant names:

• chrX-108179444-C-A
• rs201589060
• NM_033641.4:c.2132-6G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-108179444-C-A
• chrX-108179444-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_033641.4(COL4A6):​c.2132-6G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000056 in 1,177,528 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.000026 (0 hom. 12 hem.)
• Consequence: COL4A6 NM_033641.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001174
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0380
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant X-108179444-C-A is Benign according to our data. Variant chrX-108179444-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 5 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.2132-6G>T		splice_region intron	N/A	NP_378667.1	Q14031-2
	COL4A6	NM_001287758.2		c.2183-6G>T		splice_region intron	N/A	NP_001274687.1	A8MXH5
	COL4A6	NM_001847.4		c.2135-6G>T		splice_region 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.2132-6G>T		splice_region intron	N/A	ENSP00000334733.7	Q14031-2
	COL4A6	ENST00000372216.8	TSL:1	c.2135-6G>T		splice_region intron	N/A	ENSP00000361290.4	Q14031-1
	COL4A6	ENST00000621266.4	TSL:1	c.2132-6G>T		splice_region intron	N/A	ENSP00000482970.1	A0A087WZY5

Frequencies

GnomAD3 genomes AF: 0.000339 AC: 38 AN: 112120 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000940

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: 0.00

Gnomad OTH AF: 0.000665

GnomAD2 exomes AF: 0.0000661 AC: 11 AN: 166367 AF XY: 0.0000553

Gnomad AFR exome AF: 0.000868

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000263 AC: 28 AN: 1065355 Hom.: 0 Cov.: 28 AF XY: 0.0000358 AC XY: 12 AN XY: 335583

African (AFR) AF: 0.00110 AC: 28 AN: 25463

American (AMR) AF: 0.00 AC: 0 AN: 33172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18344

East Asian (EAS) AF: 0.00 AC: 0 AN: 29867

South Asian (SAS) AF: 0.00 AC: 0 AN: 50606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40059

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3121

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819957

Other (OTH) AF: 0.00 AC: 0 AN: 44766

GnomAD4 genome AF: 0.000339 AC: 38 AN: 112173 Hom.: 0 Cov.: 22 AF XY: 0.000146 AC XY: 5 AN XY: 34363

African (AFR) AF: 0.00116 AC: 36 AN: 30920

American (AMR) AF: 0.0000939 AC: 1 AN: 10652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3536

South Asian (SAS) AF: 0.00 AC: 0 AN: 2672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53207

Other (OTH) AF: 0.000657 AC: 1 AN: 1523

Alfa AF: 0.00 Hom.: 3

Bravo AF: 0.000355

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hearing loss, X-linked 6 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	1.1
DANN	Benign	0.56
PhyloP100		0.038
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs201589060; hg19: chrX-107422674;