Variant 12-79217529-G-A 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.10G>A(p.Glu4Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000555 in 1,442,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SYT1
NM_005639.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.92

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 the SYT1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 2.8351 (below the threshold of 3.09). Trascript score misZ: 4.0021 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 40, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.20192426).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYT1	NM_005639.3 link	c.10G>A	p.Glu4Lys	missense_variant	Exon 4 of 11	ENST00000261205.9	NP_005630.1	P21579A0A024RBE9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYT1	ENST00000261205.9 link	c.10G>A	p.Glu4Lys	missense_variant	Exon 4 of 11	1	NM_005639.3	ENSP00000261205.4		P21579

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000431

AC:

AN:

232270

Hom.:

AF XY:

0.00000790

AC XY:

AN XY:

126582

show subpopulations

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:

0.0000344

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000555

AC:

AN:

1442220

Hom.:

Cov.:

AF XY:

0.00000836

AC XY:

AN XY:

717832

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:

0.0000474

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10G>A (p.E4K) alteration is located in exon 5 (coding exon 1) of the SYT1 gene. This alteration results from a G to A substitution at nucleotide position 10, causing the glutamic acid (E) at amino acid position 4 to be replaced by a lysine (K). 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

0.13

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.33

T;T;.;T;T;T;T;T;T;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;.;D;D;D;.;D;D;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.20

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.77

N;N;.;.;.;.;.;N;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.070

N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.67

T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.81

T;T;T;T;T;T;T;T;T;T

Polyphen

0.98

D;D;.;.;.;.;.;D;.;.

Vest4

0.60

MutPred

0.22

Gain of catalytic residue at E4 (P = 0.0017);Gain of catalytic residue at E4 (P = 0.0017);Gain of catalytic residue at E4 (P = 0.0017);Gain of catalytic residue at E4 (P = 0.0017);Gain of catalytic residue at E4 (P = 0.0017);Gain of catalytic residue at E4 (P = 0.0017);Gain of catalytic residue at E4 (P = 0.0017);Gain of catalytic residue at E4 (P = 0.0017);Gain of catalytic residue at E4 (P = 0.0017);Gain of catalytic residue at E4 (P = 0.0017);

MVP

0.38

MPC

0.43

ClinPred

0.50

GERP RS

5.5

Varity_R

0.15

gMVP

0.56

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