rs201427270

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_003179.3(SYP):c.687C>T(p.Ala229Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000923 in 1,206,402 control chromosomes in the GnomAD database, including 4 homozygotes. There are 484 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 0.0023 ( 0 hom., 95 hem., cov: 25)

Exomes 𝑓: 0.00078 ( 4 hom. 389 hem. )

Consequence

SYP
NM_003179.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -2.32

Publications

1 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, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.012).

BP6

Variant X-49191692-G-A is Benign according to our data. Variant chrX-49191692-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198158.

BP7

Synonymous conserved (PhyloP=-2.32 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00226 (257/113504) while in subpopulation AFR AF = 0.00718 (225/31338). AF 95% confidence interval is 0.00641. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 95 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYP	NM_003179.3	MANE Select	c.687C>T	p.Ala229Ala	synonymous	Exon 6 of 7	NP_003170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYP	ENST00000263233.9	TSL:1 MANE Select	c.687C>T	p.Ala229Ala	synonymous	Exon 6 of 7	ENSP00000263233.4
SYP	ENST00000479808.5	TSL:1	c.687C>T	p.Ala229Ala	synonymous	Exon 6 of 6	ENSP00000418169.1
SYP	ENST00000472598.5	TSL:3	c.354C>T	p.Ala118Ala	synonymous	Exon 4 of 5	ENSP00000418387.1

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

257

AN:

113450

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00720

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000552

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00708

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000749

Gnomad OTH

AF:

0.00131

GnomAD2 exomes

AF:

0.00180

AC:

288

AN:

159839

AF XY:

0.00240

show subpopulations

Gnomad AFR exome

AF:

0.00765

Gnomad AMR exome

AF:

0.000263

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000894

Gnomad OTH exome

AF:

0.000988

GnomAD4 exome

AF:

0.000784

AC:

857

AN:

1092898

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

389

AN XY:

359602

show subpopulations

African (AFR)

AF:

0.00787

AC:

207

AN:

26296

American (AMR)

AF:

0.000315

AC:

AN:

34936

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19263

East Asian (EAS)

AF:

0.00

AC:

AN:

30055

South Asian (SAS)

AF:

0.00985

AC:

527

AN:

53483

European-Finnish (FIN)

AF:

0.000102

AC:

AN:

39088

Middle Eastern (MID)

AF:

0.000246

AC:

AN:

4064

European-Non Finnish (NFE)

AF:

0.0000679

AC:

AN:

839875

Other (OTH)

AF:

0.00109

AC:

AN:

45838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00226

AC:

257

AN:

113504

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

AN XY:

35640

show subpopulations

African (AFR)

AF:

0.00718

AC:

225

AN:

31338

American (AMR)

AF:

0.000551

AC:

AN:

10888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3602

South Asian (SAS)

AF:

0.00711

AC:

AN:

2814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6365

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000749

AC:

AN:

53390

Other (OTH)

AF:

0.00129

AC:

AN:

1545

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00117

Hom.:

Bravo

AF:

0.00248

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 25, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 21, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

8.0

(source)

DANN

Benign

0.95

PhyloP100

-2.3

Mutation Taster

=99/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over