X-49191618-C-T

Variant names:

• chrX-49191618-C-T
• rs961525473
• NM_003179.3:c.761G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003179.3(SYP):​c.761G>A​(p.Gly254Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,207,655 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SYP NM_003179.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.02
• Publications: 0 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.761G>A	p.Gly254Asp	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.761G>A	p.Gly254Asp	missense	Exon 6 of 7	ENSP00000263233.4	P08247-1
	SYP	ENST00000479808.5	TSL:1	c.761G>A	p.Gly254Asp	missense	Exon 6 of 6	ENSP00000418169.1	P08247-1
	SYP	ENST00000920145.1		c.749G>A	p.Gly250Asp	missense	Exon 6 of 6	ENSP00000590204.1

Frequencies

GnomAD3 genomes AF: 0.00000886 AC: 1 AN: 112924 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000322

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

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1094731 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 361085

African (AFR) AF: 0.0000380 AC: 1 AN: 26349

American (AMR) AF: 0.00 AC: 0 AN: 35002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19297

East Asian (EAS) AF: 0.00 AC: 0 AN: 30135

South Asian (SAS) AF: 0.00 AC: 0 AN: 53856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39411

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4037

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840739

Other (OTH) AF: 0.00 AC: 0 AN: 45905

GnomAD4 genome AF: 0.00000886 AC: 1 AN: 112924 Hom.: 0 Cov.: 24 AF XY: 0.0000285 AC XY: 1 AN XY: 35068

African (AFR) AF: 0.0000322 AC: 1 AN: 31078

American (AMR) AF: 0.00 AC: 0 AN: 10834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3600

South Asian (SAS) AF: 0.00 AC: 0 AN: 2779

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53248

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.7	L
PhyloP100		1.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.015	D
Sift4G	Benign	0.35	T
Polyphen		1.0	D
Vest4		0.30
MutPred		0.14		Gain of solvent accessibility (P = 0.1045)
MVP		0.85
MPC		0.59
ClinPred		0.68	D
GERP RS		5.5
Varity_R		0.37
gMVP		0.76
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs961525473; hg19: chrX-49048075;