X-49191753-A-C

Variant names:

• chrX-49191753-A-C
• rs1040270887
• NM_003179.3:c.626T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003179.3(SYP):​c.626T>G​(p.Phe209Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: SYP NM_003179.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04

Genes affected

SYP (HGNC:11506): (synaptophysin) This gene encodes an integral membrane protein of small synaptic vesicles in brain and endocrine cells. The protein also binds cholesterol and is thought to direct targeting of vesicle-associated membrane protein 2 (synaptobrevin) to intracellular compartments. Mutations in this gene are associated with an X-linked form of cognitive disability. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYP	NM_003179.3	c.626T>G	p.Phe209Cys	missense_variant	Exon 6 of 7	ENST00000263233.9	NP_003170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYP	ENST00000263233.9	c.626T>G	p.Phe209Cys	missense_variant	Exon 6 of 7	1	NM_003179.3	ENSP00000263233.4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 02, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.0078	D
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.79		Gain of catalytic residue at L210 (P = 0.0153);Gain of catalytic residue at L210 (P = 0.0153);
MVP		0.85
MPC		1.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.99

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: rs1040270887; hg19: chrX-49048210;