rs35363062

chrX-108163026-A-G

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.4082T>C(p.Leu1361Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,193,027 control chromosomes in the GnomAD database, including 197 homozygotes. There are 1,639 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (99 hom., 796 hem., cov: 23)
  • Exomes 𝑓: 0.0030 (98 hom. 843 hem.)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.429

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=0.0026853085).
• BP6: Variant X-108163026-A-G is Benign according to our data. Variant chrX-108163026-A-G is described in ClinVar as [Benign]. Clinvar id is 258278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A6	NM_033641.4	c.4082T>C	p.Leu1361Pro	missense_variant	41/45	ENST00000334504.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A6	ENST00000334504.12	c.4082T>C	p.Leu1361Pro	missense_variant	41/45	5	NM_033641.4	P4

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 3126 AN: 111284 Hom.: 99 Cov.: 23 AF XY: 0.0235 AC XY: 786 AN XY: 33504

Gnomad AFR AF: 0.0980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00873

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00115

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000321

Gnomad OTH AF: 0.0194

GnomAD3 exomes AF: 0.00844 AC: 1369 AN: 162253 Hom.: 52 AF XY: 0.00459 AC XY: 239 AN XY: 52029

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00304 AC: 3289 AN: 1081691 Hom.: 98 Cov.: 30 AF XY: 0.00240 AC XY: 843 AN XY: 351539

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.00625

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.00682

GnomAD4 genome AF: 0.0282 AC: 3138 AN: 111336 Hom.: 99 Cov.: 23 AF XY: 0.0237 AC XY: 796 AN XY: 33566

Gnomad4 AFR AF: 0.0982

Gnomad4 AMR AF: 0.00872

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000766

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000321

Gnomad4 OTH AF: 0.0192

Alfa AF: 0.00355 Hom.: 142

Bravo AF: 0.0335

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.105 AC: 403

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00954 AC: 1158

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	PreventionGenetics, part of Exact Sciences	-	- -
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. -

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	0.050
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	6.0
Dann	Benign	0.32
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.46	T;T;T;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.68	N;N;.;N;.;.
REVEL	Benign	0.16
Sift	Benign	0.49	T;T;.;T;.;.
Sift4G	Benign	0.43	T;T;T;T;T;T
Polyphen		0.0040	B;B;.;B;.;.
Vest4		0.082
MVP		0.12
MPC		0.29
ClinPred		0.00056	T
GERP RS		1.4
Varity_R		0.059
gMVP		0.21

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: rs35363062; hg19: chrX-107406256;