chrX-108159465-G-A

Variant names:

• chrX-108159465-G-A
• rs759639930
• NM_033641.4:c.4809C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_033641.4(COL4A6):​c.4809C>T​(p.Leu1603Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,210,650 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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: 0.000024 (0 hom. 5 hem.)
• Consequence: COL4A6 NM_033641.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.02
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant X-108159465-G-A is Benign according to our data. Variant chrX-108159465-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2918406.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.02 with no splicing effect.
• 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.4809C>T	p.Leu1603Leu	synonymous	Exon 44 of 45	NP_378667.1	Q14031-2
	COL4A6	NM_001287758.2		c.4860C>T	p.Leu1620Leu	synonymous	Exon 45 of 46	NP_001274687.1	A8MXH5
	COL4A6	NM_001847.4		c.4812C>T	p.Leu1604Leu	synonymous	Exon 44 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.4809C>T	p.Leu1603Leu	synonymous	Exon 44 of 45	ENSP00000334733.7	Q14031-2
	COL4A6	ENST00000372216.8	TSL:1	c.4812C>T	p.Leu1604Leu	synonymous	Exon 44 of 45	ENSP00000361290.4	Q14031-1
	COL4A6	ENST00000621266.4	TSL:1	c.4737C>T	p.Leu1579Leu	synonymous	Exon 43 of 44	ENSP00000482970.1	A0A087WZY5

Frequencies

GnomAD3 genomes AF: 0.0000621 AC: 7 AN: 112640 Hom.: 0 Cov.: 24

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: 0.00112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000715 AC: 13 AN: 181851 AF XY: 0.0000299

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000752

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000237 AC: 26 AN: 1098010 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363376

African (AFR) AF: 0.00 AC: 0 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54128

European-Finnish (FIN) AF: 0.000617 AC: 25 AN: 40499

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841995

Other (OTH) AF: 0.00 AC: 0 AN: 46087

GnomAD4 genome AF: 0.0000621 AC: 7 AN: 112640 Hom.: 0 Cov.: 24 AF XY: 0.0000863 AC XY: 3 AN XY: 34768

African (AFR) AF: 0.00 AC: 0 AN: 30975

American (AMR) AF: 0.00 AC: 0 AN: 10709

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3582

South Asian (SAS) AF: 0.00 AC: 0 AN: 2705

European-Finnish (FIN) AF: 0.00112 AC: 7 AN: 6248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53323

Other (OTH) AF: 0.00 AC: 0 AN: 1519

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.2
DANN	Benign	0.72
PhyloP100		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs759639930; hg19: chrX-107402695;