X-49191674-C-G

Variant names:

• chrX-49191674-C-G
• rs782650560
• NM_003179.3:c.705G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_003179.3(SYP):​c.705G>C​(p.Ala235Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000324 in 1,205,026 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 8 hem., cov: 25)
  • Exomes 𝑓: 0.000016 (0 hom. 4 hem.)
• Consequence: SYP NM_003179.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.983
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• non-syndromic X-linked intellectual disability

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.058).
• BP6: Variant X-49191674-C-G is Benign according to our data. Variant chrX-49191674-C-G is described in ClinVar as Benign. ClinVar VariationId is 752111.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.983 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000195 (22/112953) while in subpopulation AMR AF = 0.00166 (18/10843). AF 95% confidence interval is 0.00107. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 8 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.705G>C	p.Ala235Ala	synonymous	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.705G>C	p.Ala235Ala	synonymous	Exon 6 of 7	ENSP00000263233.4	P08247-1
	SYP	ENST00000479808.5	TSL:1	c.705G>C	p.Ala235Ala	synonymous	Exon 6 of 6	ENSP00000418169.1	P08247-1
	SYP	ENST00000920145.1		c.693G>C	p.Ala231Ala	synonymous	Exon 6 of 6	ENSP00000590204.1

Frequencies

GnomAD3 genomes AF: 0.000195 AC: 22 AN: 112901 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00166

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: 0.00197

GnomAD2 exomes AF: 0.0000625 AC: 10 AN: 159891 AF XY: 0.0000545

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000341

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: 0.000248

GnomAD4 exome AF: 0.0000156 AC: 17 AN: 1092073 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 4 AN XY: 358915

African (AFR) AF: 0.0000381 AC: 1 AN: 26272

American (AMR) AF: 0.000345 AC: 12 AN: 34801

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19226

East Asian (EAS) AF: 0.00 AC: 0 AN: 30039

South Asian (SAS) AF: 0.00 AC: 0 AN: 53510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4044

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839294

Other (OTH) AF: 0.0000874 AC: 4 AN: 45773

GnomAD4 genome AF: 0.000195 AC: 22 AN: 112953 Hom.: 0 Cov.: 25 AF XY: 0.000228 AC XY: 8 AN XY: 35149

African (AFR) AF: 0.0000321 AC: 1 AN: 31156

American (AMR) AF: 0.00166 AC: 18 AN: 10843

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53231

Other (OTH) AF: 0.00195 AC: 3 AN: 1541

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000499

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	10
DANN	Benign	0.78
PhyloP100		-0.98
Mutation Taster		=100/0	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: rs782650560; hg19: chrX-49048131;