X-38160935-C-A

Position:

• chrX-38160935-C-A

Variant summary

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

The NM_006307.5(SRPX):​c.773G>T​(p.Arg258Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SRPX NM_006307.5 missense, splice_region
• Scores: Splicing: ADA: 0.05387
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65

Genes affected

SRPX (HGNC:11309): (sushi repeat containing protein X-linked) Predicted to be an extracellular matrix structural constituent. Predicted to be involved in cell adhesion. Predicted to act upstream of or within several processes, including negative regulation of cell proliferation involved in contact inhibition; phagolysosome assembly; and positive regulation of extrinsic apoptotic signaling pathway in absence of ligand. Part of collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRPX	NM_006307.5	c.773G>T	p.Arg258Ile	missense_variant, splice_region_variant	6/10	ENST00000378533.4	NP_006298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRPX	ENST00000378533.4	c.773G>T	p.Arg258Ile	missense_variant, splice_region_variant	6/10	1	NM_006307.5	ENSP00000367794	P2
SRPX	ENST00000544439.5	c.713G>T	p.Arg238Ile	missense_variant, splice_region_variant	5/9	2		ENSP00000440758	A2
SRPX	ENST00000432886.6	c.596G>T	p.Arg199Ile	missense_variant, splice_region_variant	5/9	2		ENSP00000411165
SRPX	ENST00000538295.5	c.773G>T	p.Arg258Ile	missense_variant, splice_region_variant	6/9	2		ENSP00000445034

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

The c.773G>T (p.R258I) alteration is located in exon 6 (coding exon 6) of the SRPX gene. This alteration results from a G to T substitution at nucleotide position 773, causing the arginine (R) at amino acid position 258 to be replaced by an isoleucine (I). 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	0.17
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	.;.;.;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.98	.;.;.;D
Vest4		0.45
MutPred		0.54		.;.;Gain of methylation at K260 (P = 0.0365);Gain of methylation at K260 (P = 0.0365);
MVP		0.90
MPC		0.084
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.62
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.054
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.090		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-38020188;