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

1
8
8
Splicing: ADA: 0.05387
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.65
Variant links:
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]

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ACMG classification

Classification made for transcript

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
SRPXNM_006307.5 linkuse as main transcriptc.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
SRPXENST00000378533.4 linkuse as main transcriptc.773G>T p.Arg258Ile missense_variant, splice_region_variant 6/101 NM_006307.5 ENSP00000367794 P2P78539-1
SRPXENST00000544439.5 linkuse as main transcriptc.713G>T p.Arg238Ile missense_variant, splice_region_variant 5/92 ENSP00000440758 A2P78539-5
SRPXENST00000432886.6 linkuse as main transcriptc.596G>T p.Arg199Ile missense_variant, splice_region_variant 5/92 ENSP00000411165 P78539-3
SRPXENST00000538295.5 linkuse as main transcriptc.773G>T p.Arg258Ile missense_variant, splice_region_variant 6/92 ENSP00000445034 P78539-4

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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 17, 2023The 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; API