rs1042065

chrX-108190458-A-CchrX-108190458-A-GchrX-108190458-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033641.4(COL4A6):c.1360T>G(p.Ser454Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S454P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.091958135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A6	NM_033641.4	c.1360T>G	p.Ser454Ala	missense_variant	20/45	ENST00000334504.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A6	ENST00000334504.12	c.1360T>G	p.Ser454Ala	missense_variant	20/45	5	NM_033641.4	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.7
Dann	Benign	0.85
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.011	T;T;T;T;T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.092	T;T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.33	N;N;.;N;.;N
REVEL	Benign	0.24
Sift	Benign	0.16	T;T;.;T;.;T
Sift4G	Benign	0.30	T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;B
Vest4		0.063
MutPred		0.089		.;Loss of glycosylation at S455 (P = 0.0024);.;.;.;.;
MVP		0.29
MPC		0.15
ClinPred		0.064	T
GERP RS		0.71
Varity_R		0.061
gMVP		0.22

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: COSV57877639;