rs148735447

Variant names:

• chrX-100666781-C-T
• rs148735447
• NM_014467.3:c.809C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_014467.3(SRPX2):​c.809C>T​(p.Pro270Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000479 in 1,210,823 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 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).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., 8 hem., cov: 24)
  • Exomes 𝑓: 0.000025 (0 hom. 6 hem.)
• Consequence: SRPX2 NM_014467.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.62

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3072214).
• BP6: Variant X-100666781-C-T is Benign according to our data. Variant chrX-100666781-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207383.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRPX2	NM_014467.3	c.809C>T	p.Pro270Leu	missense_variant	Exon 8 of 11	ENST00000373004.5	NP_055282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRPX2	ENST00000373004.5	c.809C>T	p.Pro270Leu	missense_variant	Exon 8 of 11	1	NM_014467.3	ENSP00000362095.3

Frequencies

GnomAD3 genomes AF: 0.000266 AC: 30 AN: 112575 Hom.: 0 Cov.: 24 AF XY: 0.000230 AC XY: 8 AN XY: 34723

Gnomad AFR AF: 0.000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 21 AN: 183344 Hom.: 0 AF XY: 0.0000737 AC XY: 5 AN XY: 67806

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000255 AC: 28 AN: 1098192 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 6 AN XY: 363550

Gnomad4 AFR exome AF: 0.000909

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.000266 AC: 30 AN: 112631 Hom.: 0 Cov.: 24 AF XY: 0.000230 AC XY: 8 AN XY: 34789

Gnomad4 AFR AF: 0.000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.000321

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.809C>T (p.P270L) alteration is located in exon 8 (coding exon 7) of the SRPX2 gene. This alteration results from a C to T substitution at nucleotide position 809, causing the proline (P) at amino acid position 270 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Apr 27, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked Benign:1

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.2	D;.
REVEL	Uncertain	0.57
Sift	Benign	0.040	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.77
MVP		0.76
MPC		0.68
ClinPred		0.23	T
GERP RS		5.6
Varity_R		0.66
gMVP		0.90

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: rs148735447; hg19: chrX-99921778;