Variant chr12-79285960-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_005639.3(SYT1):c.340A>T(p.Met114Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,453,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SYT1
NM_005639.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86

Variant links:

Genes affected

SYT1 (HGNC:11509): (synaptotagmin 1) This gene encodes a member of the synaptotagmin protein family. The synaptotagmins are integral membrane proteins of synaptic vesicles that serve as calcium sensors in the process of vesicular trafficking and exocytosis. The encoded protein participates in triggering neurotransmitter release at the synapse in response to calcium binding. Mutations in this gene are associated with Baker-Gordon syndrome. [provided by RefSeq, Jan 2023]

SYT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYT1. . Gene score misZ 2.8351 (greater than the threshold 3.09). Trascript score misZ 4.0021 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.11661464).

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYT1	NM_005639.3 linkuse as main transcript	c.340A>T	p.Met114Leu	missense_variant	5/11	ENST00000261205.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYT1	ENST00000261205.9 linkuse as main transcript	c.340A>T	p.Met114Leu	missense_variant	5/11	1	NM_005639.3	P3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1453896

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

723024

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.340A>T (p.M114L) alteration is located in exon 6 (coding exon 2) of the SYT1 gene. This alteration results from a A to T substitution at nucleotide position 340, causing the methionine (M) at amino acid position 114 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.34

T;T;.;T;T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

0.018

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.66

.;.;T;T;T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.12

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

N;N;.;N;.;.

MutationTaster

Benign

0.98

D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.080

N;N;N;N;N;N

REVEL

Benign

0.046

Sift

Benign

0.50

T;T;T;T;T;T

Sift4G

Benign

0.59

T;T;T;T;T;T

Polyphen

0.0

B;B;.;B;.;.

Vest4

0.32

MutPred

0.39

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MVP

0.082

MPC

0.23

ClinPred

0.70

GERP RS

5.6

Varity_R

0.16

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over