X-108175676-A-G

Variant names:

• chrX-108175676-A-G
• rs4623610
• NM_033641.4:c.2808T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_033641.4(COL4A6):​c.2808T>C​(p.Arg936Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (37790 hom., 31144 hem., cov: 21)
  • Exomes 𝑓: 1.0 (366039 hom. 360845 hem.)
  • Failed GnomAD Quality Control
• Consequence: COL4A6 NM_033641.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.661
• Publications: 19 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-108175676-A-G is Benign according to our data. Variant chrX-108175676-A-G is described in ClinVar as Benign. ClinVar VariationId is 258270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.661 with no splicing effect.

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.2808T>C	p.Arg936Arg	synonymous	Exon 29 of 45	NP_378667.1	Q14031-2
	COL4A6	NM_001287758.2		c.2859T>C	p.Arg953Arg	synonymous	Exon 30 of 46	NP_001274687.1	A8MXH5
	COL4A6	NM_001847.4		c.2811T>C	p.Arg937Arg	synonymous	Exon 29 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.2808T>C	p.Arg936Arg	synonymous	Exon 29 of 45	ENSP00000334733.7	Q14031-2
	COL4A6	ENST00000372216.8	TSL:1	c.2811T>C	p.Arg937Arg	synonymous	Exon 29 of 45	ENSP00000361290.4	Q14031-1
	COL4A6	ENST00000621266.4	TSL:1	c.2808T>C	p.Arg936Arg	synonymous	Exon 29 of 44	ENSP00000482970.1	A0A087WZY5

Frequencies

GnomAD3 genomes AF: 0.986 AC: 107755 AN: 109254 Hom.: 37795 Cov.: 21

Gnomad AFR AF: 0.953

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.993

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.990

GnomAD2 exomes AF: 0.996 AC: 177999 AN: 178727 AF XY: 0.997

Gnomad AFR exome AF: 0.950

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.999 AC: 1093996 AN: 1095545 Hom.: 366039 Cov.: 31 AF XY: 0.999 AC XY: 360845 AN XY: 361261

African (AFR) AF: 0.952 AC: 25005 AN: 26269

American (AMR) AF: 0.997 AC: 34622 AN: 34712

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 19323 AN: 19323

East Asian (EAS) AF: 1.00 AC: 30174 AN: 30174

South Asian (SAS) AF: 1.00 AC: 53587 AN: 53598

European-Finnish (FIN) AF: 1.00 AC: 40515 AN: 40515

Middle Eastern (MID) AF: 0.999 AC: 4122 AN: 4127

European-Non Finnish (NFE) AF: 1.00 AC: 840817 AN: 840841

Other (OTH) AF: 0.997 AC: 45831 AN: 45986

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.986 AC: 107797 AN: 109295 Hom.: 37790 Cov.: 21 AF XY: 0.988 AC XY: 31144 AN XY: 31507

African (AFR) AF: 0.953 AC: 28536 AN: 29943

American (AMR) AF: 0.993 AC: 10205 AN: 10278

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2611 AN: 2611

East Asian (EAS) AF: 1.00 AC: 3430 AN: 3430

South Asian (SAS) AF: 1.00 AC: 2379 AN: 2379

European-Finnish (FIN) AF: 1.00 AC: 5662 AN: 5662

Middle Eastern (MID) AF: 1.00 AC: 214 AN: 214

European-Non Finnish (NFE) AF: 1.00 AC: 52622 AN: 52626

Other (OTH) AF: 0.991 AC: 1464 AN: 1478

Alfa AF: 0.984 Hom.: 20474

Bravo AF: 0.985

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Hearing loss, X-linked 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.50
DANN	Benign	0.39
PhyloP100		-0.66
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: rs4623610; hg19: chrX-107418906; COSMIC: COSV108166924;