X-49191502-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003179.3(SYP):c.877G>A(p.Gly293Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00123 in 1,210,400 control chromosomes in the GnomAD database, including 3 homozygotes. There are 493 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 0.0011 (1 hom., 34 hem., cov: 24)
  • Exomes 𝑓: 0.0012 (2 hom. 459 hem.)
• Consequence: SYP NM_003179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 4.39

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060765147).
• BP6: Variant X-49191502-C-T is Benign according to our data. Variant chrX-49191502-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 368465.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=2}. Variant chrX-49191502-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00115 (130/113139) while in subpopulation NFE AF= 0.00171 (91/53344). AF 95% confidence interval is 0.00142. There are 1 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYP	NM_003179.3	c.877G>A	p.Gly293Ser	missense_variant	6/7	ENST00000263233.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYP	ENST00000263233.9	c.877G>A	p.Gly293Ser	missense_variant	6/7	1	NM_003179.3	P1

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 130 AN: 113085 Hom.: 1 Cov.: 24 AF XY: 0.000965 AC XY: 34 AN XY: 35225

Gnomad AFR AF: 0.0000963

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000741

Gnomad ASJ AF: 0.00301

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00131

GnomAD3 exomes AF: 0.00126 AC: 224 AN: 177311 Hom.: 2 AF XY: 0.00102 AC XY: 66 AN XY: 64715

Gnomad AFR exome AF: 0.0000808

Gnomad AMR exome AF: 0.000184

Gnomad ASJ exome AF: 0.00448

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000531

Gnomad FIN exome AF: 0.00503

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00123 AC: 1353 AN: 1097261 Hom.: 2 Cov.: 31 AF XY: 0.00126 AC XY: 459 AN XY: 362953

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.00464

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000555

Gnomad4 FIN exome AF: 0.00438

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00115 AC: 130 AN: 113139 Hom.: 1 Cov.: 24 AF XY: 0.000963 AC XY: 34 AN XY: 35289

Gnomad4 AFR AF: 0.0000961

Gnomad4 AMR AF: 0.000741

Gnomad4 ASJ AF: 0.00301

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00288

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.00129

Alfa AF: 0.00177 Hom.: 72

Bravo AF: 0.000839

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00134 AC: 9

ExAC AF: 0.00111 AC: 134

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -

History of neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2012

There is insufficient or conflicting evidence for classification of this alteration. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Benign	0.94
DEOGEN2	Benign	0.30	T;T
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.0061	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.94	L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.42	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.86	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0050	B;B
Vest4		0.43
MVP		0.60
MPC		0.45
ClinPred		0.032	T
GERP RS		2.8
Varity_R		0.098
gMVP		0.42

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: rs139475570; hg19: chrX-49047959;