rs201427270

chrX-49191692-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_003179.3(SYP):c.687C>T(p.Ala229=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000923 in 1,206,402 control chromosomes in the GnomAD database, including 4 homozygotes. There are 484 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., 95 hem., cov: 25)
  • Exomes 𝑓: 0.00078 (4 hom. 389 hem.)
• Consequence: SYP NM_003179.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -2.32

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant X-49191692-G-A is Benign according to our data. Variant chrX-49191692-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198158.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BP7: Synonymous conserved (PhyloP=-2.32 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00226 (257/113504) while in subpopulation AFR AF= 0.00718 (225/31338). AF 95% confidence interval is 0.00641. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 95 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYP	NM_003179.3	c.687C>T	p.Ala229=	synonymous_variant	6/7	ENST00000263233.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYP	ENST00000263233.9	c.687C>T	p.Ala229=	synonymous_variant	6/7	1	NM_003179.3	P1

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 257 AN: 113450 Hom.: 0 Cov.: 25 AF XY: 0.00267 AC XY: 95 AN XY: 35576

Gnomad AFR AF: 0.00720

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000552

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00708

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000749

Gnomad OTH AF: 0.00131

GnomAD3 exomes AF: 0.00180 AC: 288 AN: 159839 Hom.: 0 AF XY: 0.00240 AC XY: 133 AN XY: 55409

Gnomad AFR exome AF: 0.00765

Gnomad AMR exome AF: 0.000263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000894

Gnomad OTH exome AF: 0.000988

GnomAD4 exome AF: 0.000784 AC: 857 AN: 1092898 Hom.: 4 Cov.: 31 AF XY: 0.00108 AC XY: 389 AN XY: 359602

Gnomad4 AFR exome AF: 0.00787

Gnomad4 AMR exome AF: 0.000315

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00985

Gnomad4 FIN exome AF: 0.000102

Gnomad4 NFE exome AF: 0.0000679

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00226 AC: 257 AN: 113504 Hom.: 0 Cov.: 25 AF XY: 0.00267 AC XY: 95 AN XY: 35640

Gnomad4 AFR AF: 0.00718

Gnomad4 AMR AF: 0.000551

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00711

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000749

Gnomad4 OTH AF: 0.00129

Alfa AF: 0.00117 Hom.: 4

Bravo AF: 0.00248

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	8.0
Dann	Benign	0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs201427270; hg19: chrX-49048149;