dbSNP rs961525473: SYP:p.Gly254Val (chrX-49191618-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_003179.3(SYP):c.761G>T(p.Gly254Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,094,731 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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. G254D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

SYP
NM_003179.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.02

Publications

0 publications found

Variant links:

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

SYP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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>T	p.Gly254Val	missense	Exon 6 of 7	NP_003170.1	P08247-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYP	ENST00000263233.9	TSL:1 MANE Select	c.761G>T	p.Gly254Val	missense	Exon 6 of 7	ENSP00000263233.4	P08247-1
SYP	ENST00000479808.5	TSL:1	c.761G>T	p.Gly254Val	missense	Exon 6 of 6	ENSP00000418169.1	P08247-1
SYP	ENST00000920145.1		c.749G>T	p.Gly250Val	missense	Exon 6 of 6	ENSP00000590204.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1094731

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361085

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26349

American (AMR)

AF:

0.00

AC:

AN:

35002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19297

East Asian (EAS)

AF:

0.00

AC:

AN:

30135

South Asian (SAS)

AF:

0.00

AC:

AN:

53856

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39411

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4037

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

840739

Other (OTH)

AF:

0.00

AC:

AN:

45905

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.63

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

0.83

PhyloP100

1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.46

Sift

Benign

0.084

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.46

MutPred

0.24

Loss of loop (P = 0.0073)

MVP

0.87

MPC

0.57

ClinPred

0.71

GERP RS

5.5

Varity_R

0.39

gMVP

0.74

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over