X-49191502-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003179.3(SYP):c.877G>A(p.Gly293Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00123 in 1,210,400 control chromosomes in the GnomAD database, including 3 homozygotes. There are 493 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., 34 hem., cov: 24)

Exomes 𝑓: 0.0012 ( 2 hom. 459 hem. )

Consequence

SYP
NM_003179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 4.39

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060765147).

BP6

Variant X-49191502-C-T is Benign according to our data. Variant chrX-49191502-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 368465.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2}. Variant chrX-49191502-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00115 (130/113139) while in subpopulation NFE AF= 0.00171 (91/53344). AF 95% confidence interval is 0.00142. There are 1 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYP	NM_003179.3 link	c.877G>A	p.Gly293Ser	missense_variant	Exon 6 of 7	ENST00000263233.9	NP_003170.1	P08247-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYP	ENST00000263233.9 link	c.877G>A	p.Gly293Ser	missense_variant	Exon 6 of 7	1	NM_003179.3	ENSP00000263233.4		P08247-1

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

130

AN:

113085

Hom.:

Cov.:

AF XY:

0.000965

AC XY:

AN XY:

35225

show subpopulations

Gnomad AFR

AF:

0.0000963

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000741

Gnomad ASJ

AF:

0.00301

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00288

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.00131

GnomAD3 exomes

AF:

0.00126

AC:

224

AN:

177311

Hom.:

AF XY:

0.00102

AC XY:

AN XY:

64715

show subpopulations

Gnomad AFR exome

AF:

0.0000808

Gnomad AMR exome

AF:

0.000184

Gnomad ASJ exome

AF:

0.00448

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000531

Gnomad FIN exome

AF:

0.00503

Gnomad NFE exome

AF:

0.00130

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00123

AC:

1353

AN:

1097261

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

459

AN XY:

362953

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00464

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000555

Gnomad4 FIN exome

AF:

0.00438

Gnomad4 NFE exome

AF:

0.00122

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.00115

AC:

130

AN:

113139

Hom.:

Cov.:

AF XY:

0.000963

AC XY:

AN XY:

35289

show subpopulations

Gnomad4 AFR

AF:

0.0000961

Gnomad4 AMR

AF:

0.000741

Gnomad4 ASJ

AF:

0.00301

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00288

Gnomad4 NFE

AF:

0.00171

Gnomad4 OTH

AF:

0.00129

Alfa

AF:

0.00177

Hom.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00138

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00134

AC:

ExAC

AF:

0.00111

AC:

134

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Jun 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

History of neurodevelopmental disorder

Uncertain:1

Sep 12, 2012

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

not specified

Benign:1

Oct 10, 2019

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.30

T;T

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

.;D

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.94

L;L

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.42

N;N

REVEL

Uncertain

0.29

Sift

Benign

0.86

T;T

Sift4G

Benign

0.61

T;T

Polyphen

0.0050

B;B

Vest4

0.43

MVP

0.60

MPC

0.45

ClinPred

0.032

GERP RS

2.8

Varity_R

0.098

gMVP

0.42

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

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