Genetic Variant SYP:c.36+5G>A (chrX-49200146-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003179.3(SYP):c.36+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000019 in 1,051,769 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )

Consequence

SYP
NM_003179.3 splice_region, intron

Scores

Splicing: ADA: 0.9993

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

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.36+5G>A		splice_region intron	N/A	NP_003170.1	P08247-1
	SYP-AS1	NR_046649.1		n.386+922C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SYP	ENST00000263233.9	TSL:1 MANE Select	c.36+5G>A	splice_region intron	N/A	ENSP00000263233.4	P08247-1
SYP	ENST00000479808.5	TSL:1	c.36+5G>A	splice_region intron	N/A	ENSP00000418169.1	P08247-1
SYP	ENST00000920145.1		c.36+5G>A	splice_region intron	N/A	ENSP00000590204.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

105270

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000190

AC:

AN:

1051769

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

343511

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000405

AC:

AN:

24662

American (AMR)

AF:

0.00

AC:

AN:

27840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18560

East Asian (EAS)

AF:

0.00

AC:

AN:

26940

South Asian (SAS)

AF:

0.00

AC:

AN:

49763

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37073

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4026

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

818643

Other (OTH)

AF:

0.0000226

AC:

AN:

44262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

3.7

PromoterAI

-0.16

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.72

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over