rs2295912

Variant names:

• chrX-108170700-G-A
• rs2295912
• NM_033641.4:c.3402C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033641.4(COL4A6):​c.3402C>T​(p.Ala1134Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,204,103 control chromosomes in the GnomAD database, including 600 homozygotes. There are 11,102 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 (207 hom., 1616 hem., cov: 24)
  • Exomes 𝑓: 0.027 (393 hom. 9486 hem.)
• Consequence: COL4A6 NM_033641.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0930
• Publications: 5 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), ClinGen, Ambry Genetics, PanelApp Australia
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-108170700-G-A is Benign according to our data. Variant chrX-108170700-G-A is described in ClinVar as Benign. ClinVar VariationId is 258274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.093 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A6	NM_033641.4	MANE Select	c.3402C>T	p.Ala1134Ala	synonymous	Exon 35 of 45	NP_378667.1
	COL4A6	NM_001287758.2		c.3453C>T	p.Ala1151Ala	synonymous	Exon 36 of 46	NP_001274687.1
	COL4A6	NM_001847.4		c.3405C>T	p.Ala1135Ala	synonymous	Exon 35 of 45	NP_001838.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A6	ENST00000334504.12	TSL:5 MANE Select	c.3402C>T	p.Ala1134Ala	synonymous	Exon 35 of 45	ENSP00000334733.7
	COL4A6	ENST00000372216.8	TSL:1	c.3405C>T	p.Ala1135Ala	synonymous	Exon 35 of 45	ENSP00000361290.4
	COL4A6	ENST00000621266.4	TSL:1	c.3402C>T	p.Ala1134Ala	synonymous	Exon 35 of 44	ENSP00000482970.1

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 5683 AN: 111817 Hom.: 206 Cov.: 24

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0969

Gnomad AMR AF: 0.0379

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.0804

Gnomad SAS AF: 0.0479

Gnomad FIN AF: 0.00767

Gnomad MID AF: 0.0211

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0559

GnomAD2 exomes AF: 0.0365 AC: 6480 AN: 177302 AF XY: 0.0334

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0455

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.0836

Gnomad FIN exome AF: 0.00631

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0226

GnomAD4 exome AF: 0.0265 AC: 28952 AN: 1092231 Hom.: 393 Cov.: 30 AF XY: 0.0264 AC XY: 9486 AN XY: 358957

African (AFR) AF: 0.116 AC: 3021 AN: 25986

American (AMR) AF: 0.0458 AC: 1559 AN: 34012

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 318 AN: 19189

East Asian (EAS) AF: 0.0794 AC: 2395 AN: 30146

South Asian (SAS) AF: 0.0461 AC: 2447 AN: 53075

European-Finnish (FIN) AF: 0.00761 AC: 308 AN: 40466

Middle Eastern (MID) AF: 0.0299 AC: 123 AN: 4107

European-Non Finnish (NFE) AF: 0.0205 AC: 17244 AN: 839431

Other (OTH) AF: 0.0335 AC: 1537 AN: 45819

GnomAD4 genome AF: 0.0508 AC: 5688 AN: 111872 Hom.: 207 Cov.: 24 AF XY: 0.0474 AC XY: 1616 AN XY: 34080

African (AFR) AF: 0.119 AC: 3661 AN: 30746

American (AMR) AF: 0.0377 AC: 399 AN: 10571

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 39 AN: 2648

East Asian (EAS) AF: 0.0801 AC: 284 AN: 3547

South Asian (SAS) AF: 0.0473 AC: 126 AN: 2664

European-Finnish (FIN) AF: 0.00767 AC: 47 AN: 6131

Middle Eastern (MID) AF: 0.0231 AC: 5 AN: 216

European-Non Finnish (NFE) AF: 0.0184 AC: 977 AN: 53145

Other (OTH) AF: 0.0552 AC: 84 AN: 1523

Alfa AF: 0.0346 Hom.: 2055

Bravo AF: 0.0580

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Hearing loss, X-linked 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.1
DANN	Benign	0.41
PhyloP100		0.093
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: rs2295912; hg19: chrX-107413930; COSMIC: COSV57861634;