X-49200182-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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).

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

Publications

3 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 links:

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

SYP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 212359.

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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

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.:

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

GnomAD2 exomes

AF:

0.000125

AC:

AN:

103834

AF XY:

0.000172

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 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

African (AFR)

AF:

0.00

AC:

AN:

24513

American (AMR)

AF:

0.00

AC:

AN:

27802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18514

East Asian (EAS)

AF:

0.00

AC:

AN:

26843

South Asian (SAS)

AF:

0.00

AC:

AN:

49673

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37213

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4013

European-Non Finnish (NFE)

AF:

0.000232

AC:

190

AN:

818296

Other (OTH)

AF:

0.000181

AC:

AN:

44224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000133

AC:

AN:

112790

Hom.:

Cov.:

AF XY:

0.0000858

AC XY:

AN XY:

34982

show subpopulations

African (AFR)

AF:

0.0000642

AC:

AN:

31137

American (AMR)

AF:

0.00

AC:

AN:

10801

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3533

South Asian (SAS)

AF:

0.00

AC:

AN:

2797

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6215

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000244

AC:

AN:

53221

Other (OTH)

AF:

0.00

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

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

PhyloP100

1.4

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

PromoterAI

0.16

Neutral

(source)

Varity_R

0.35

gMVP

0.68

Mutation Taster

=297/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over