rs35179844

chrX-108170822-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033641.4(COL4A6):c.3373C>T(p.Pro1125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,210,551 control chromosomes in the GnomAD database, including 317 homozygotes. There are 2,183 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (167 hom., 1068 hem., cov: 23)
  • Exomes 𝑓: 0.0038 (150 hom. 1115 hem.)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.88

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035195649).
• BP6: Variant X-108170822-G-A is Benign according to our data. Variant chrX-108170822-G-A is described in ClinVar as [Benign]. Clinvar id is 258273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A6	NM_033641.4	c.3373C>T	p.Pro1125Ser	missense_variant	34/45	ENST00000334504.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A6	ENST00000334504.12	c.3373C>T	p.Pro1125Ser	missense_variant	34/45	5	NM_033641.4	P4

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 3883 AN: 112729 Hom.: 167 Cov.: 23 AF XY: 0.0304 AC XY: 1059 AN XY: 34885

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00109

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000506

Gnomad OTH AF: 0.0262

GnomAD3 exomes AF: 0.0105 AC: 1919 AN: 183216 Hom.: 74 AF XY: 0.00700 AC XY: 474 AN XY: 67702

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.00740

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000420

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000294

Gnomad OTH exome AF: 0.00420

GnomAD4 exome AF: 0.00375 AC: 4122 AN: 1097769 Hom.: 150 Cov.: 31 AF XY: 0.00307 AC XY: 1115 AN XY: 363127

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.00824

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000351

Gnomad4 FIN exome AF: 0.0000493

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.00851

GnomAD4 genome AF: 0.0345 AC: 3896 AN: 112782 Hom.: 167 Cov.: 23 AF XY: 0.0306 AC XY: 1068 AN XY: 34948

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000727

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000506

Gnomad4 OTH AF: 0.0259

Alfa AF: 0.0135 Hom.: 885

Bravo AF: 0.0400

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.121 AC: 463

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0113 AC: 1377

EpiCase AF: 0.000600

EpiControl AF: 0.000296

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	Jan 08, 2018	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	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -

Hearing loss, X-linked 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	14
Dann	Benign	0.62
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T;T;D;D;T;T
MetaRNN	Benign	0.0035	T;T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N;N;.;N;.;N
REVEL	Uncertain	0.29
Sift	Benign	0.42	T;T;.;T;.;T
Sift4G	Benign	0.10	T;T;D;D;T;T
Polyphen		0.12	B;B;.;B;.;B
Vest4		0.099
MPC		0.50
ClinPred		0.0078	T
GERP RS		2.3
Varity_R		0.044
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35179844; hg19: chrX-107414052;