rs121918363

chrX-100667292-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014467.3(SRPX2):c.980A>G(p.Asn327Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,209,994 control chromosomes in the GnomAD database, including 2 homozygotes. There are 334 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N327K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., 12 hem., cov: 24)
  • Exomes 𝑓: 0.00092 (2 hom. 322 hem.)
• Consequence: SRPX2 NM_014467.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 1.70

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04739812).
• BS2: High Hemizygotes in GnomAd at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRPX2	NM_014467.3	c.980A>G	p.Asn327Ser	missense_variant	9/11	ENST00000373004.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRPX2	ENST00000373004.5	c.980A>G	p.Asn327Ser	missense_variant	9/11	1	NM_014467.3	P1

Frequencies

GnomAD3 genomes AF: 0.000402 AC: 45 AN: 111823 Hom.: 0 Cov.: 24 AF XY: 0.000353 AC XY: 12 AN XY: 33993

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000946

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000752

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000572 AC: 105 AN: 183471 Hom.: 1 AF XY: 0.000383 AC XY: 26 AN XY: 67905

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000919 AC: 1009 AN: 1098171 Hom.: 2 Cov.: 31 AF XY: 0.000886 AC XY: 322 AN XY: 363529

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000370

Gnomad4 NFE exome AF: 0.00116

Gnomad4 OTH exome AF: 0.000369

GnomAD4 genome AF: 0.000402 AC: 45 AN: 111823 Hom.: 0 Cov.: 24 AF XY: 0.000353 AC XY: 12 AN XY: 33993

Gnomad4 AFR AF: 0.000130

Gnomad4 AMR AF: 0.0000946

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000752

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000769 Hom.: 34

Bravo AF: 0.000374

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 11

ExAC AF: 0.000469 AC: 57

EpiCase AF: 0.000709

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SRPX2 p.N327S variant was identified in 2 of 348 proband chromosomes (frequency: 0.0057) from individuals or families with Rolandic epilepsy (RE) and atypical RE and was present in 1 of 806 control chromosomes (frequency: 0.0012) from healthy individuals (Reinthaler_2014_PMID:24995671). Reinthaler et al. (2014) suggested the p.N327S variant does not play a major role in RE. The p.N327S variant was identified in a three generation family with atypical RE, verbal dyspraxia and cognitive impairment of variable degrees (Roll_2006_PMID:16497722). However a potentially deleterious variant, p.A716T, in the GRIN2A gene was found in a subsequent study of this family that segregated in all affected individuals (Lesca_2013_PMID:23933820). All but 2 affected family members with the SRPX2 mutation also carried the GRIN2A mutation, and all patients with the GRIN2A mutation had seizures, whereas the 2 patients with only the SRPX2 mutation and not the GRIN2A mutation did not have seizures (Lesca_2013_PMID:23933820). In another study, the p.N327S variant was identified in a boy with language and intellectual difficulties (Chen_2017_PMID:28440294). The variant was identified in dbSNP (ID: rs121918363), LOVD 3.0 (classified as likely benign) and in ClinVar (classified as benign by Invitae, likely benign by Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen and as uncertain significance by EGL Genetics, Swiss Institute of Bioinformatics, GeneDx and Genetic Services Laboratory, University of Chicago). The variant was identified in control databases in 111 of 205296 chromosomes (1 homozygous; 27 hemizygous) at a frequency of 0.000541 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 104 of 92730 chromosomes (freq: 0.001122), Other in 1 of 5338 chromosomes (freq: 0.000187), African in 3 of 18978 chromosomes (freq: 0.000158), European (Finnish) in 2 of 18621 chromosomes (freq: 0.000107) and Latino in 1 of 28049 chromosomes (freq: 0.000036), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity.The p.Asn327 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. Using an in utero Srpx2 silencing approach in mouse models, the expression of the mutant p.N327S-SRPX2 protein was found to lead to impaired development of the cerebral cortex and post-natal epileptiform activity (Salmi_2013_PMID:23831613). The p.N327S mutation was also shown to lead to gain-of-glycosylation of the mutant SRPX2 protein which causes partial retentionof the altered protein within the endoplasmic reticulumin a transfected-cell model (Roll_2006_PMID:16497722). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2018	p.Asn327Ser (AAC>AGC): c.980 A>G in exon 9 in the SRPX2 gene (NM_014467.2).The N327S variant in the SRPX2 gene has been reported previously in association with Rolandic seizures and intellectual disability (Roll et al., 2006). The N327S variant segregated with the phenotype in multiple family members and results in a gain-of-function glycosylation that likely disrupts protein folding and function. However, Piton et al. later questioned the pathogenicity of the N327S variant because of the frequency in control populations (2013). The NHLBI ESP Exome Sequencing Project reports N327S was observed in 0.16% (11/6728) alleles from individuals of European background, including 3 hemizygous males. The N327S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N327S as a variant of unknown significance, which may be related to the reported brain malformation. The variant is found in ,SRPX2 panel(s). -

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

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Rolandic epilepsy, mental retardation, and speech dyspraxia, X-linked, in X-linked Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:24995671) (PMID:23871722). PS3-Supporting => PS3 downgraded in strength to Supporting (PMID:16497722). -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Aug 01, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 02, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.063	T;.
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.64	A
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.39	N;.
REVEL	Benign	0.080
Sift	Benign	0.036	D;.
Sift4G	Benign	0.14	T;.
Polyphen		0.063	B;.
Vest4		0.69
MVP		0.43
MPC		0.13
ClinPred		0.047	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.21

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: rs121918363; hg19: chrX-99922289;