Variant X-49191497-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_003179.3(SYP):c.882C>G(p.Asp294Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000826 in 1,210,379 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

SYP
NM_003179.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0100

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2168453).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000707 (8/113101) while in subpopulation AFR AF= 0.000257 (8/31150). AF 95% confidence interval is 0.000127. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYP	NM_003179.3 linkuse as main transcript	c.882C>G	p.Asp294Glu	missense_variant	6/7	ENST00000263233.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYP	ENST00000263233.9 linkuse as main transcript	c.882C>G	p.Asp294Glu	missense_variant	6/7	1	NM_003179.3	P1	P08247-1

Frequencies

GnomAD3 genomes

AF:

0.0000707

AC:

AN:

113101

Hom.:

Cov.:

AF XY:

0.0000851

AC XY:

AN XY:

35235

show subpopulations

Gnomad AFR

AF:

0.000257

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

GnomAD3 exomes

AF:

0.0000113

AC:

AN:

177687

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

64819

show subpopulations

Gnomad AFR exome

AF:

0.000160

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097278

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362944

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000707

AC:

AN:

113101

Hom.:

Cov.:

AF XY:

0.0000851

AC XY:

AN XY:

35235

show subpopulations

Gnomad4 AFR

AF:

0.000257

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, X-linked 96

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.51

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.23

T;T

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.040

N;N

MutationTaster

Benign

0.74

D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.24

N;N

REVEL

Benign

0.19

Sift

Benign

0.26

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.15

MutPred

0.17

Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);

MVP

0.43

MPC

0.42

ClinPred

0.051

GERP RS

3.0

Varity_R

0.12

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over