X-49200182-A-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_003179.3(SYP):c.5T>A(p.Leu2Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,163,881 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 78 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). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.00019 ( 0 hom. 75 hem. )

Consequence

SYP
NM_003179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.37

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:

SYP-AS1 (HGNC:40571): (SYP antisense RNA 1)

SYP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24262035).

BP6

Variant X-49200182-A-T is Benign according to our data. Variant chrX-49200182-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212359.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000133 (15/112790) while in subpopulation NFE AF= 0.000244 (13/53221). AF 95% confidence interval is 0.000144. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYP	NM_003179.3 link	c.5T>A	p.Leu2Gln	missense_variant	Exon 1 of 7	ENST00000263233.9	NP_003170.1	P08247-1
SYP-AS1	NR_046649.1 link	n.386+958A>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYP	ENST00000263233.9 link	c.5T>A	p.Leu2Gln	missense_variant	Exon 1 of 7	1	NM_003179.3	ENSP00000263233.4		P08247-1

Frequencies

GnomAD3 genomes

AF:

0.000133

AC:

AN:

112790

Hom.:

Cov.:

AF XY:

0.0000858

AC XY:

AN XY:

34982

show subpopulations

Gnomad AFR

AF:

0.0000642

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:

0.000244

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000125

AC:

AN:

103834

Hom.:

AF XY:

0.000172

AC XY:

AN XY:

34798

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000348

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000188

AC:

198

AN:

1051091

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

AN XY:

342891

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000232

Gnomad4 OTH exome

AF:

0.000181

GnomAD4 genome

AF:

0.000133

AC:

AN:

112790

Hom.:

Cov.:

AF XY:

0.0000858

AC XY:

AN XY:

34982

show subpopulations

Gnomad4 AFR

AF:

0.0000642

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:

0.000244

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000280

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.000136

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 06, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYP: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;T

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.55

.;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.070

N;N

REVEL

Benign

0.16

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.98

D;D

Vest4

0.23

MVP

0.21

MPC

0.57

ClinPred

0.18

GERP RS

3.3

Varity_R

0.35

gMVP

0.68

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