X-108190458-A-G

Variant names:

• chrX-108190458-A-G
• rs1042065
• NM_033641.4:c.1360T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_033641.4(COL4A6):​c.1360T>C​(p.Ser454Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.71 (20132 hom., 22369 hem., cov: 22)
  • Exomes 𝑓: 0.75 (211417 hom. 269654 hem.)
  • Failed GnomAD Quality Control
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0770
• Publications: 29 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.5844543E-5).
• BP6: Variant X-108190458-A-G is Benign according to our data. Variant chrX-108190458-A-G is described in ClinVar as Benign. ClinVar VariationId is 258267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4	c.1360T>C	p.Ser454Pro	missense_variant	Exon 20 of 45	ENST00000334504.12	NP_378667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A6	ENST00000334504.12	c.1360T>C	p.Ser454Pro	missense_variant	Exon 20 of 45	5	NM_033641.4	ENSP00000334733.7

Frequencies

GnomAD3 genomes AF: 0.708 AC: 77520 AN: 109499 Hom.: 20129 Cov.: 22

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.812

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.776

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.715

GnomAD2 exomes AF: 0.671 AC: 120387 AN: 179408 AF XY: 0.679

Gnomad AFR exome AF: 0.640

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.806

Gnomad EAS exome AF: 0.383

Gnomad FIN exome AF: 0.860

Gnomad NFE exome AF: 0.790

Gnomad OTH exome AF: 0.714

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.750 AC: 820094 AN: 1093512 Hom.: 211417 Cov.: 29 AF XY: 0.748 AC XY: 269654 AN XY: 360458

African (AFR) AF: 0.638 AC: 16740 AN: 26226

American (AMR) AF: 0.393 AC: 13753 AN: 34954

Ashkenazi Jewish (ASJ) AF: 0.812 AC: 15645 AN: 19265

East Asian (EAS) AF: 0.330 AC: 9957 AN: 30155

South Asian (SAS) AF: 0.620 AC: 33264 AN: 53635

European-Finnish (FIN) AF: 0.854 AC: 34530 AN: 40433

Middle Eastern (MID) AF: 0.791 AC: 3249 AN: 4105

European-Non Finnish (NFE) AF: 0.786 AC: 659228 AN: 838824

Other (OTH) AF: 0.735 AC: 33728 AN: 45915

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.708 AC: 77547 AN: 109554 Hom.: 20132 Cov.: 22 AF XY: 0.703 AC XY: 22369 AN XY: 31842

African (AFR) AF: 0.644 AC: 19350 AN: 30053

American (AMR) AF: 0.505 AC: 5186 AN: 10270

Ashkenazi Jewish (ASJ) AF: 0.812 AC: 2112 AN: 2602

East Asian (EAS) AF: 0.379 AC: 1310 AN: 3460

South Asian (SAS) AF: 0.595 AC: 1482 AN: 2492

European-Finnish (FIN) AF: 0.863 AC: 4955 AN: 5742

Middle Eastern (MID) AF: 0.769 AC: 166 AN: 216

European-Non Finnish (NFE) AF: 0.788 AC: 41386 AN: 52552

Other (OTH) AF: 0.720 AC: 1076 AN: 1494

Alfa AF: 0.751 Hom.: 100085

Bravo AF: 0.679

TwinsUK AF: 0.773 AC: 2867

ALSPAC AF: 0.774 AC: 2235

ESP6500AA AF: 0.651 AC: 2496

ESP6500EA AF: 0.795 AC: 5348

ExAC AF: 0.689 AC: 83647

EpiCase AF: 0.782

EpiControl AF: 0.788

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.9
DANN	Benign	0.84
DEOGEN2	Benign	0.038	.;T;.;.;T;T
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.0097	T;T;T;T;T;T
MetaRNN	Benign	0.000046	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.4	.;N;.;.;.;.
PhyloP100		0.077
PrimateAI	Benign	0.32	T
PROVEAN	Benign	2.6	N;N;.;N;.;N
REVEL	Benign	0.22
Sift	Benign	1.0	T;T;.;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;B
Vest4		0.058
MPC		0.23
ClinPred		0.0086	T
GERP RS		0.71
Varity_R		0.088
gMVP		0.49
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: rs1042065; hg19: chrX-107433688; COSMIC: COSV57861753;