rs145388022

Variant names:

• chrX-108165418-C-A
• rs145388022
• NM_033641.4:c.3760G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-108165418-C-A
• chrX-108165418-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_033641.4(COL4A6):​c.3760G>T​(p.Ala1254Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00945 in 1,207,467 control chromosomes in the GnomAD database, including 78 homozygotes. There are 3,783 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (1 hom., 296 hem., cov: 24)
  • Exomes 𝑓: 0.0096 (77 hom. 3487 hem.)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.168
• 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), 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005559027).
• BP6: Variant X-108165418-C-A is Benign according to our data. Variant chrX-108165418-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 296 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.3760G>T	p.Ala1254Ser	missense	Exon 38 of 45	NP_378667.1	Q14031-2
	COL4A6	NM_001287758.2		c.3811G>T	p.Ala1271Ser	missense	Exon 39 of 46	NP_001274687.1	A8MXH5
	COL4A6	NM_001847.4		c.3763G>T	p.Ala1255Ser	missense	Exon 38 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.3760G>T	p.Ala1254Ser	missense	Exon 38 of 45	ENSP00000334733.7	Q14031-2
	COL4A6	ENST00000372216.8	TSL:1	c.3763G>T	p.Ala1255Ser	missense	Exon 38 of 45	ENSP00000361290.4	Q14031-1
	COL4A6	ENST00000621266.4	TSL:1	c.3688G>T	p.Ala1230Ser	missense	Exon 37 of 44	ENSP00000482970.1	A0A087WZY5

Frequencies

GnomAD3 genomes AF: 0.00794 AC: 888 AN: 111771 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.00124

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00341

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00115

Gnomad FIN AF: 0.0427

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00396

GnomAD2 exomes AF: 0.00978 AC: 1757 AN: 179672 AF XY: 0.00955

Gnomad AFR exome AF: 0.000916

Gnomad AMR exome AF: 0.000999

Gnomad ASJ exome AF: 0.00374

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0456

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00675

GnomAD4 exome AF: 0.00961 AC: 10528 AN: 1095642 Hom.: 77 Cov.: 30 AF XY: 0.00965 AC XY: 3487 AN XY: 361426

African (AFR) AF: 0.00103 AC: 27 AN: 26338

American (AMR) AF: 0.00112 AC: 39 AN: 34958

Ashkenazi Jewish (ASJ) AF: 0.00354 AC: 68 AN: 19225

East Asian (EAS) AF: 0.00 AC: 0 AN: 30189

South Asian (SAS) AF: 0.00355 AC: 190 AN: 53539

European-Finnish (FIN) AF: 0.0415 AC: 1680 AN: 40479

Middle Eastern (MID) AF: 0.00165 AC: 6 AN: 3642

European-Non Finnish (NFE) AF: 0.00974 AC: 8192 AN: 841305

Other (OTH) AF: 0.00709 AC: 326 AN: 45967

GnomAD4 genome AF: 0.00794 AC: 888 AN: 111825 Hom.: 1 Cov.: 24 AF XY: 0.00870 AC XY: 296 AN XY: 34007

African (AFR) AF: 0.00123 AC: 38 AN: 30780

American (AMR) AF: 0.00132 AC: 14 AN: 10635

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 9 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3521

South Asian (SAS) AF: 0.00115 AC: 3 AN: 2605

European-Finnish (FIN) AF: 0.0427 AC: 261 AN: 6118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0104 AC: 554 AN: 53090

Other (OTH) AF: 0.00391 AC: 6 AN: 1534

Alfa AF: 0.00943 Hom.: 405

Bravo AF: 0.00512

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.0107 AC: 31

ESP6500AA AF: 0.00261 AC: 10

ESP6500EA AF: 0.0109 AC: 73

ExAC AF: 0.00928 AC: 1127

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0056	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.055	N
PhyloP100		-0.17
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	0.96	T
Polyphen		0.77	P
Vest4		0.080
MVP		0.63
MPC		0.31
ClinPred		0.024	T
GERP RS		3.4
Varity_R		0.12
gMVP		0.070
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: rs145388022; hg19: chrX-107408648; COSMIC: COSV106100494; COSMIC: COSV106100494;