X-49200182-A-G

Variant names:

• chrX-49200182-A-G
• rs200470034
• NM_003179.3:c.5T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003179.3(SYP):​c.5T>C​(p.Leu2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,051,090 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 2 hem.)
• Consequence: SYP NM_003179.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• Publications: 3 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYP	NM_003179.3	c.5T>C	p.Leu2Pro	missense_variant	Exon 1 of 7	ENST00000263233.9	NP_003170.1
SYP-AS1	NR_046649.1	n.386+958A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYP	ENST00000263233.9	c.5T>C	p.Leu2Pro	missense_variant	Exon 1 of 7	1	NM_003179.3	ENSP00000263233.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000963 AC: 1 AN: 103834 AF XY: 0.0000287

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000524

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: 2 AN: 1051090 Hom.: 0 Cov.: 30 AF XY: 0.00000583 AC XY: 2 AN XY: 342890

African (AFR) AF: 0.00 AC: 0 AN: 24513

American (AMR) AF: 0.0000360 AC: 1 AN: 27802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18514

East Asian (EAS) AF: 0.00 AC: 0 AN: 26843

South Asian (SAS) AF: 0.00 AC: 0 AN: 49673

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37213

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4013

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 818295

Other (OTH) AF: 0.0000226 AC: 1 AN: 44224

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.45	.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		1.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.15	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;D
Vest4		0.34
MutPred		0.43		Gain of catalytic residue at L2 (P = 0.0021);Gain of catalytic residue at L2 (P = 0.0021);
MVP		0.26
MPC		0.84
ClinPred		0.46	T
GERP RS		3.3
PromoterAI		0.14	Neutral
Varity_R		0.28
gMVP		0.75
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs200470034; hg19: chrX-49056641;