dbSNP rs1303115956: SYP:p.Met1? (chrX-49200184-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_ModerateBS2

The NM_003179.3(SYP):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000859 in 1,163,896 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000038 ( 0 hom. 0 hem. )

Consequence

SYP
NM_003179.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.16

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 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: Likely_benign. The variant received -2 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 7 codons. Genomic position: 49200168. Lost 0.020 part of the original CDS.

BS2

High Hemizygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYP	NM_003179.3	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 7	NP_003170.1	P08247-1
	SYP-AS1	NR_046649.1		n.386+960C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYP	ENST00000263233.9	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 7	ENSP00000263233.4	P08247-1
SYP	ENST00000479808.5	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 1 of 6	ENSP00000418169.1	P08247-1
SYP	ENST00000920145.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 6	ENSP00000590204.1

Frequencies

GnomAD3 genomes

AF:

0.0000531

AC:

AN:

112921

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

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

GnomAD2 exomes

AF:

0.00000964

AC:

AN:

103773

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000174

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000381

AC:

AN:

1050975

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

342787

show subpopulations

African (AFR)

AF:

0.0000816

AC:

AN:

24505

American (AMR)

AF:

0.00

AC:

AN:

27801

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18519

East Asian (EAS)

AF:

0.00

AC:

AN:

26834

South Asian (SAS)

AF:

0.00

AC:

AN:

49655

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3999

European-Non Finnish (NFE)

AF:

0.00000122

AC:

AN:

818238

Other (OTH)

AF:

0.0000226

AC:

AN:

44212

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

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:

0.0000531

AC:

AN:

112921

Hom.:

Cov.:

AF XY:

0.0000570

AC XY:

AN XY:

35091

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

31156

American (AMR)

AF:

0.00

AC:

AN:

10812

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3548

South Asian (SAS)

AF:

0.00

AC:

AN:

2811

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6247

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53255

Other (OTH)

AF:

0.00

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00

Hom.:

Bravo

AF:

0.0000529

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-1.1

PhyloP100

1.2

PROVEAN

Benign

-0.17

REVEL

Benign

0.24

Sift

Benign

0.054

Sift4G

Benign

0.15

Polyphen

0.0

Vest4

0.52

MutPred

0.97

Gain of sheet (P = 0.0344)

MVP

0.67

ClinPred

0.85

GERP RS

3.3

PromoterAI

0.24

Neutral

(source)

Varity_R

0.35

gMVP

0.49

Mutation Taster

=96/104

disease causing

(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

Computational scores

Splicing

Publications

Other links and lift over