rs373847965

chrX-100664867-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014467.3(SRPX2):c.449C>T(p.Ser150Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,208,869 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00017 (0 hom. 75 hem.)
• Consequence: SRPX2 NM_014467.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.285

Genes affected

SRPX2 (HGNC:30668): (sushi repeat containing protein X-linked 2) This gene encodes a secreted protein that contains three sushi repeat motifs. The encoded protein may play a role in the development of speech and language centers in the brain. This protein may also be involved in angiogenesis. Mutations in this gene are the cause of bilateral perisylvian polymicrogyria, rolandic epilepsy, speech dyspraxia and cognitive disability. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013480395).
• BP6: Variant X-100664867-C-T is Benign according to our data. Variant chrX-100664867-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 380310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100664867-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRPX2	NM_014467.3	c.449C>T	p.Ser150Phe	missense_variant	5/11	ENST00000373004.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRPX2	ENST00000373004.5	c.449C>T	p.Ser150Phe	missense_variant	5/11	1	NM_014467.3	P1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 25 AN: 112325 Hom.: 0 Cov.: 23 AF XY: 0.000174 AC XY: 6 AN XY: 34485

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

Gnomad ASJ AF: 0.00339

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.000393 AC: 70 AN: 178297 Hom.: 0 AF XY: 0.000456 AC XY: 29 AN XY: 63643

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000958

Gnomad ASJ exome AF: 0.00216

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000277

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000171 AC: 187 AN: 1096487 Hom.: 0 Cov.: 32 AF XY: 0.000207 AC XY: 75 AN XY: 362059

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.00258

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000932

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.000587

GnomAD4 genome AF: 0.000222 AC: 25 AN: 112382 Hom.: 0 Cov.: 23 AF XY: 0.000174 AC XY: 6 AN XY: 34552

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00339

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000188

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.000928 Hom.: 6

Bravo AF: 0.000336

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000445 AC: 54

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	SRPX2: BP4, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2015	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2016	- -

Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;.
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.37	T;T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.5	D;.;.
REVEL	Benign	0.16
Sift	Uncertain	0.0060	D;.;.
Sift4G	Uncertain	0.014	D;.;.
Polyphen		0.13	B;.;.
Vest4		0.41
MVP		0.45
MPC		0.18
ClinPred		0.038	T
GERP RS		4.7
Varity_R		0.40
gMVP		0.43

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: rs373847965; hg19: chrX-99919864;