12-79285960-A-T

Position:

• chr12-79285960-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

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]

ACMG classification

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	Protein	UniProt
SYT1	NM_005639.3	c.340A>T	p.Met114Leu	missense_variant	5/11	ENST00000261205.9	NP_005630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYT1	ENST00000261205.9	c.340A>T	p.Met114Leu	missense_variant	5/11	1	NM_005639.3	ENSP00000261205	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1453896 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 723024

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
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	D
LIST_S2	Benign	0.66	.;.;T;T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;N;.;N;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.71	T
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	D
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

Other links and lift over

dbSNP: rs1879292660; hg19: chr12-79679740;