12-79292034-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005639.3(SYT1):c.378T>C(p.Thr126=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,613,946 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (31 hom.)
• Consequence: SYT1 NM_005639.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.338

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 12-79292034-T-C is Benign according to our data. Variant chr12-79292034-T-C is described in ClinVar as [Benign]. Clinvar id is 790668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.338 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1564/152176) while in subpopulation AFR AF= 0.0294 (1221/41516). AF 95% confidence interval is 0.028. There are 19 homozygotes in gnomad4. There are 733 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1554 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYT1	NM_005639.3	c.378T>C	p.Thr126=	synonymous_variant	6/11	ENST00000261205.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYT1	ENST00000261205.9	c.378T>C	p.Thr126=	synonymous_variant	6/11	1	NM_005639.3	P3

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1554 AN: 152058 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00649

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00449 AC: 1129 AN: 251236 Hom.: 6 AF XY: 0.00406 AC XY: 551 AN XY: 135784

Gnomad AFR exome AF: 0.0296

Gnomad AMR exome AF: 0.00547

Gnomad ASJ exome AF: 0.00923

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00833

GnomAD4 exome AF: 0.00288 AC: 4208 AN: 1461770 Hom.: 31 Cov.: 31 AF XY: 0.00283 AC XY: 2056 AN XY: 727182

Gnomad4 AFR exome AF: 0.0315

Gnomad4 AMR exome AF: 0.00613

Gnomad4 ASJ exome AF: 0.00873

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00151

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.00172

Gnomad4 OTH exome AF: 0.00657

GnomAD4 genome AF: 0.0103 AC: 1564 AN: 152176 Hom.: 19 Cov.: 32 AF XY: 0.00985 AC XY: 733 AN XY: 74386

Gnomad4 AFR AF: 0.0294

Gnomad4 AMR AF: 0.00648

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00632 Hom.: 2

Bravo AF: 0.0118

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00373

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

SYT1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	0.21
Dann	Benign	0.71

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: rs34404568; hg19: chr12-79685814;