X-108157014-T-C

Variant names:

• chrX-108157014-T-C
• NM_033641.4:c.5059A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033641.4(COL4A6):​c.5059A>G​(p.Met1687Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38976806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4	c.5059A>G	p.Met1687Val	missense_variant	Exon 45 of 45	ENST00000334504.12	NP_378667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A6	ENST00000334504.12	c.5059A>G	p.Met1687Val	missense_variant	Exon 45 of 45	5	NM_033641.4	ENSP00000334733.7

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5062A>G (p.M1688V) alteration is located in exon 45 (coding exon 45) of the COL4A6 gene. This alteration results from a A to G substitution at nucleotide position 5062, causing the methionine (M) at amino acid position 1688 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Uncertain	0.71	.;D;.;.;D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;T;T;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.39	T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	2.0	.;M;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D;D;.;D;.;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.015	D;D;.;D;.;.
Sift4G	Benign	0.11	T;T;T;T;T;T
Polyphen		0.081	B;B;.;B;.;.
Vest4		0.26
MutPred		0.68		.;Gain of methylation at K1689 (P = 0.0162);.;.;.;.;
MVP		0.86
MPC		0.19
ClinPred		0.31	T
GERP RS		4.3
Varity_R		0.48
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-107400244;