X-49191755-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003179.3(SYP):c.624C>T(p.Gly208=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,204,931 control chromosomes in the GnomAD database, including 1 homozygotes. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (1 hom., 5 hem., cov: 25)
  • Exomes 𝑓: 0.00010 (0 hom. 39 hem.)
• Consequence: SYP NM_003179.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.177

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-49191755-G-A is Benign according to our data. Variant chrX-49191755-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 725059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.177 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000167 (19/113466) while in subpopulation NFE AF= 0.000243 (13/53400). AF 95% confidence interval is 0.000143. There are 1 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYP	NM_003179.3	c.624C>T	p.Gly208=	synonymous_variant	6/7	ENST00000263233.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYP	ENST00000263233.9	c.624C>T	p.Gly208=	synonymous_variant	6/7	1	NM_003179.3	P1

Frequencies

GnomAD3 genomes AF: 0.000168 AC: 19 AN: 113410 Hom.: 1 Cov.: 25 AF XY: 0.000141 AC XY: 5 AN XY: 35544

Gnomad AFR AF: 0.0000640

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000922

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000474

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000243

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000102 AC: 16 AN: 157419 Hom.: 0 AF XY: 0.0000938 AC XY: 5 AN XY: 53323

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000701

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000248

GnomAD4 exome AF: 0.000102 AC: 111 AN: 1091465 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 39 AN XY: 358415

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000205

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.0000436

GnomAD4 genome AF: 0.000167 AC: 19 AN: 113466 Hom.: 1 Cov.: 25 AF XY: 0.000140 AC XY: 5 AN XY: 35610

Gnomad4 AFR AF: 0.0000639

Gnomad4 AMR AF: 0.0000921

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000474

Gnomad4 NFE AF: 0.000243

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000254 Hom.: 2

Bravo AF: 0.0000642

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 04, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	11
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782692341; hg19: chrX-49048212;