rs112034997

Variant names:

• chrX-108176874-C-A
• rs112034997
• NM_033641.4:c.2653G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_033641.4(COL4A6):​c.2653G>T​(p.Val885Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,209,619 control chromosomes in the GnomAD database, including 5 homozygotes. There are 134 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., 54 hem., cov: 24)
  • Exomes 𝑓: 0.00023 (4 hom. 80 hem.)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.509
• 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), 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064350367).
• BP6: Variant X-108176874-C-A is Benign according to our data. Variant chrX-108176874-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445729.
• BS2: High Hemizygotes in GnomAd4 at 54 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A6	NM_033641.4	MANE Select	c.2653G>T	p.Val885Phe	missense	Exon 28 of 45	NP_378667.1
	COL4A6	NM_001287758.2		c.2704G>T	p.Val902Phe	missense	Exon 29 of 46	NP_001274687.1
	COL4A6	NM_001847.4		c.2656G>T	p.Val886Phe	missense	Exon 28 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.2653G>T	p.Val885Phe	missense	Exon 28 of 45	ENSP00000334733.7
	COL4A6	ENST00000372216.8	TSL:1	c.2656G>T	p.Val886Phe	missense	Exon 28 of 45	ENSP00000361290.4
	COL4A6	ENST00000621266.4	TSL:1	c.2653G>T	p.Val885Phe	missense	Exon 28 of 44	ENSP00000482970.1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 140 AN: 112978 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000836

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000364

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00262

GnomAD2 exomes AF: 0.000409 AC: 74 AN: 180805 AF XY: 0.000229

Gnomad AFR exome AF: 0.00397

Gnomad AMR exome AF: 0.000778

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000233 AC: 255 AN: 1096586 Hom.: 4 Cov.: 30 AF XY: 0.000221 AC XY: 80 AN XY: 362456

African (AFR) AF: 0.00470 AC: 124 AN: 26357

American (AMR) AF: 0.000883 AC: 31 AN: 35125

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19324

East Asian (EAS) AF: 0.00 AC: 0 AN: 30166

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3494

European-Non Finnish (NFE) AF: 0.00000713 AC: 6 AN: 841743

Other (OTH) AF: 0.00202 AC: 93 AN: 45995

GnomAD4 genome AF: 0.00132 AC: 149 AN: 113033 Hom.: 1 Cov.: 24 AF XY: 0.00154 AC XY: 54 AN XY: 35175

African (AFR) AF: 0.00433 AC: 135 AN: 31155

American (AMR) AF: 0.000835 AC: 9 AN: 10774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.000365 AC: 1 AN: 2739

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6279

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53404

Other (OTH) AF: 0.00259 AC: 4 AN: 1547

Alfa AF: 0.000247 Hom.: 11

Bravo AF: 0.00176

ESP6500AA AF: 0.00443 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000395 AC: 48

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	COL4A6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.69
DANN	Benign	0.89
DEOGEN2	Uncertain	0.42	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0064	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	-0.045	N
PhyloP100		-0.51
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.38
Sift	Benign	0.085	T
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.21
MVP		0.42
MPC		0.72
ClinPred		0.062	T
GERP RS		-4.6
Varity_R		0.11
gMVP		0.19
Mutation Taster		=99/1	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: rs112034997; hg19: chrX-107420104;