chrX-49191510-C-T

Variant names:

• chrX-49191510-C-T
• rs587780477
• NM_003179.3:c.869G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_003179.3(SYP):​c.869G>A​(p.Gly290Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G290W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: SYP NM_003179.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.474
• Publications: 0 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 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-49191510-C-T is Benign according to our data. Variant chrX-49191510-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 130532.Status of the report is criteria_provided_single_submitter, 1 stars.

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.869G>A	p.Gly290Glu	missense	Exon 6 of 7	NP_003170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYP	ENST00000263233.9	TSL:1 MANE Select	c.869G>A	p.Gly290Glu	missense	Exon 6 of 7	ENSP00000263233.4
	SYP	ENST00000479808.5	TSL:1	c.869G>A	p.Gly290Glu	missense	Exon 6 of 6	ENSP00000418169.1
	SYP	ENST00000920145.1		c.857G>A	p.Gly286Glu	missense	Exon 6 of 6	ENSP00000590204.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.019	D
MutationAssessor	Benign	1.2	L
PhyloP100		0.47
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.022	D
Sift4G	Benign	0.097	T
Polyphen		1.0	D
Vest4		0.46
MutPred		0.20		Gain of solvent accessibility (P = 0.0766)
MVP		0.80
MPC		0.58
ClinPred		0.50	D
GERP RS		4.9
Varity_R		0.21
gMVP		0.53
Mutation Taster		=77/23	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: rs587780477; hg19: chrX-49047967;