X-49191691-C-T

Variant names:

• chrX-49191691-C-T
• rs782424574
• NM_003179.3:c.688G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The NM_003179.3(SYP):​c.688G>A​(p.Ala230Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000458 in 1,091,953 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: SYP NM_003179.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.38
• 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, STRONG, LIMITED Submitted by: Illumina, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37935656).
• BP6: Variant X-49191691-C-T is Benign according to our data. Variant chrX-49191691-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3452125.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 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.688G>A	p.Ala230Thr	missense	Exon 6 of 7	NP_003170.1	P08247-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYP	ENST00000263233.9	TSL:1 MANE Select	c.688G>A	p.Ala230Thr	missense	Exon 6 of 7	ENSP00000263233.4	P08247-1
	SYP	ENST00000479808.5	TSL:1	c.688G>A	p.Ala230Thr	missense	Exon 6 of 6	ENSP00000418169.1	P08247-1
	SYP	ENST00000920145.1		c.676G>A	p.Ala226Thr	missense	Exon 6 of 6	ENSP00000590204.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.0000252 AC: 4 AN: 158671 AF XY: 0.0000183

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000151

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: 0.00000458 AC: 5 AN: 1091953 Hom.: 0 Cov.: 31 AF XY: 0.00000557 AC XY: 2 AN XY: 358851

African (AFR) AF: 0.00 AC: 0 AN: 26281

American (AMR) AF: 0.000115 AC: 4 AN: 34865

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19244

East Asian (EAS) AF: 0.00 AC: 0 AN: 29998

South Asian (SAS) AF: 0.00 AC: 0 AN: 53411

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38999

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4057

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839329

Other (OTH) AF: 0.0000218 AC: 1 AN: 45769

GnomAD4 genome Cov.: 25

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000844 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.10
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.058	T
Polyphen		1.0	D
Vest4		0.31
MutPred		0.38		Gain of glycosylation at A230 (P = 0.0312)
MVP		0.24
MPC		1.0
ClinPred		0.59	D
GERP RS		5.5
Varity_R		0.28
gMVP		0.84
Mutation Taster		=87/13	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: rs782424574; hg19: chrX-49048148;