X-108190458-A-G

Position:

• chrX-108190458-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 258267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108190458-A-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A6	NM_033641.4	c.1360T>C	p.Ser454Pro	missense_variant	20/45	ENST00000334504.12	NP_378667.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.708 AC: 77520 AN: 109499 Hom.: 20129 Cov.: 22 AF XY: 0.703 AC XY: 22335 AN XY: 31775

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

GnomAD3 exomes AF: 0.671 AC: 120387 AN: 179408 Hom.: 27593 AF XY: 0.679 AC XY: 43762 AN XY: 64412

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 SAS exome AF: 0.603

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

Gnomad4 AFR exome AF: 0.638

Gnomad4 AMR exome AF: 0.393

Gnomad4 ASJ exome AF: 0.812

Gnomad4 EAS exome AF: 0.330

Gnomad4 SAS exome AF: 0.620

Gnomad4 FIN exome AF: 0.854

Gnomad4 NFE exome AF: 0.786

Gnomad4 OTH exome AF: 0.735

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

Gnomad4 AFR AF: 0.644

Gnomad4 AMR AF: 0.505

Gnomad4 ASJ AF: 0.812

Gnomad4 EAS AF: 0.379

Gnomad4 SAS AF: 0.595

Gnomad4 FIN AF: 0.863

Gnomad4 NFE AF: 0.788

Gnomad4 OTH AF: 0.720

Alfa AF: 0.762 Hom.: 84647

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hearing loss, X-linked 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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;.;.;.;.
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1042065; hg19: chrX-107433688; COSMIC: COSV57861753;