rs34466065

Variant names:

• chrX-108170621-T-C
• rs34466065
• NM_033641.4:c.3481A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-108170621-T-C
• chrX-108170621-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033641.4(COL4A6):​c.3481A>G​(p.Ile1161Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0542 in 1,201,111 control chromosomes in the GnomAD database, including 1,369 homozygotes. There are 20,788 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (74 hom., 1214 hem., cov: 23)
  • Exomes 𝑓: 0.056 (1295 hom. 19574 hem.)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.422
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030541122).
• BP6: Variant X-108170621-T-C is Benign according to our data. Variant chrX-108170621-T-C is described in ClinVar as Benign. ClinVar VariationId is 258275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0604 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.3481A>G	p.Ile1161Val	missense	Exon 35 of 45	NP_378667.1
	COL4A6	NM_001287758.2		c.3532A>G	p.Ile1178Val	missense	Exon 36 of 46	NP_001274687.1
	COL4A6	NM_001847.4		c.3484A>G	p.Ile1162Val	missense	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.3481A>G	p.Ile1161Val	missense	Exon 35 of 45	ENSP00000334733.7
	COL4A6	ENST00000372216.8	TSL:1	c.3484A>G	p.Ile1162Val	missense	Exon 35 of 45	ENSP00000361290.4
	COL4A6	ENST00000621266.4	TSL:1	c.3481A>G	p.Ile1161Val	missense	Exon 35 of 44	ENSP00000482970.1

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 4345 AN: 112011 Hom.: 74 Cov.: 23

Gnomad AFR AF: 0.00862

Gnomad AMI AF: 0.0146

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0442

Gnomad EAS AF: 0.000559

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.0513

Gnomad NFE AF: 0.0622

Gnomad OTH AF: 0.0441

GnomAD2 exomes AF: 0.0405 AC: 7050 AN: 174213 AF XY: 0.0409

Gnomad AFR exome AF: 0.00887

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.0436

Gnomad EAS exome AF: 0.000151

Gnomad FIN exome AF: 0.0435

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0508

GnomAD4 exome AF: 0.0558 AC: 60752 AN: 1089045 Hom.: 1295 Cov.: 30 AF XY: 0.0549 AC XY: 19574 AN XY: 356793

African (AFR) AF: 0.00780 AC: 202 AN: 25884

American (AMR) AF: 0.0231 AC: 763 AN: 33044

Ashkenazi Jewish (ASJ) AF: 0.0431 AC: 822 AN: 19054

East Asian (EAS) AF: 0.000166 AC: 5 AN: 30182

South Asian (SAS) AF: 0.0205 AC: 1072 AN: 52245

European-Finnish (FIN) AF: 0.0433 AC: 1753 AN: 40481

Middle Eastern (MID) AF: 0.103 AC: 413 AN: 4004

European-Non Finnish (NFE) AF: 0.0636 AC: 53341 AN: 838416

Other (OTH) AF: 0.0521 AC: 2381 AN: 45735

GnomAD4 genome AF: 0.0388 AC: 4346 AN: 112066 Hom.: 74 Cov.: 23 AF XY: 0.0355 AC XY: 1214 AN XY: 34244

African (AFR) AF: 0.00860 AC: 266 AN: 30929

American (AMR) AF: 0.0290 AC: 308 AN: 10610

Ashkenazi Jewish (ASJ) AF: 0.0442 AC: 117 AN: 2650

East Asian (EAS) AF: 0.000561 AC: 2 AN: 3567

South Asian (SAS) AF: 0.0147 AC: 39 AN: 2657

European-Finnish (FIN) AF: 0.0366 AC: 224 AN: 6126

Middle Eastern (MID) AF: 0.0514 AC: 11 AN: 214

European-Non Finnish (NFE) AF: 0.0622 AC: 3303 AN: 53112

Other (OTH) AF: 0.0436 AC: 66 AN: 1514

Alfa AF: 0.0549 Hom.: 3073

Bravo AF: 0.0360

TwinsUK AF: 0.0553 AC: 205

ALSPAC AF: 0.0585 AC: 169

ESP6500AA AF: 0.0107 AC: 41

ESP6500EA AF: 0.0632 AC: 425

ExAC AF: 0.0407 AC: 4939

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 27, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 16, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Hearing loss, X-linked 6 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.2
DANN	Benign	0.45
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.39	N
PhyloP100		-0.42
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.14
Sift	Benign	0.58	T
Sift4G	Benign	0.36	T
Polyphen		0.015	B
Vest4		0.048
MPC		0.20
ClinPred		0.0025	T
GERP RS		-2.0
Varity_R		0.038
gMVP		0.37
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: rs34466065; hg19: chrX-107413851;