chrX-49191511-C-T

Variant names:

• chrX-49191511-C-T
• rs376222680
• NM_003179.3:c.868G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003179.3(SYP):​c.868G>A​(p.Gly290Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,210,064 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G290W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SYP NM_003179.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13

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 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 rank	MANE	Protein	UniProt
SYP	NM_003179.3	c.868G>A	p.Gly290Arg	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.868G>A	p.Gly290Arg	missense_variant	Exon 6 of 7	1	NM_003179.3	ENSP00000263233.4

Frequencies

GnomAD3 genomes AF: 0.00000885 AC: 1 AN: 113041 Hom.: 0 Cov.: 24 AF XY: 0.0000284 AC XY: 1 AN XY: 35173

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000356

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1097023 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362809

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000885 AC: 1 AN: 113041 Hom.: 0 Cov.: 24 AF XY: 0.0000284 AC XY: 1 AN XY: 35173

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000356

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	.;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.79	N;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.047	D;D
Polyphen		1.0	D;D
Vest4		0.49
MutPred		0.23		Gain of solvent accessibility (P = 0.0971);Gain of solvent accessibility (P = 0.0971);
MVP		0.75
MPC		0.54
ClinPred		0.61	D
GERP RS		4.9
Varity_R		0.34
gMVP		0.54

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: rs376222680; hg19: chrX-49047968; COSMIC: COSV54294262; COSMIC: COSV54294262;