chrX-49191511-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in 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
• Publications: 1 publications found

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]

SYP Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 96

  Inheritance: XL Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Illumina, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYP	NM_003179.3	MANE Select	c.868G>A	p.Gly290Arg	missense	Exon 6 of 7	NP_003170.1	P08247-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYP	ENST00000263233.9	TSL:1 MANE Select	c.868G>A	p.Gly290Arg	missense	Exon 6 of 7	ENSP00000263233.4	P08247-1
	SYP	ENST00000479808.5	TSL:1	c.868G>A	p.Gly290Arg	missense	Exon 6 of 6	ENSP00000418169.1	P08247-1
	SYP	ENST00000920145.1		c.856G>A	p.Gly286Arg	missense	Exon 6 of 6	ENSP00000590204.1

Frequencies

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

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

African (AFR) AF: 0.00 AC: 0 AN: 26392

American (AMR) AF: 0.00 AC: 0 AN: 35176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19366

East Asian (EAS) AF: 0.00 AC: 0 AN: 30184

South Asian (SAS) AF: 0.00 AC: 0 AN: 54033

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841900

Other (OTH) AF: 0.00 AC: 0 AN: 46004

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

African (AFR) AF: 0.00 AC: 0 AN: 31121

American (AMR) AF: 0.00 AC: 0 AN: 10795

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3604

South Asian (SAS) AF: 0.000356 AC: 1 AN: 2810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53343

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.23		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
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

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