chr12-79448958-T-C

Variant names:

• chr12-79448958-T-C
• rs1135402761
• NM_005639.3:c.1103T>C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_005639.3(SYT1):​c.1103T>C​(p.Ile368Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYT1 NM_005639.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.01

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]

ENSG00000257894 (HGNC:58105):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a region_of_interest Phospholipid binding (size 246) in uniprot entity SYT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005639.3
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 12-79448958-T-C is Pathogenic according to our data. Variant chr12-79448958-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-79448958-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYT1	NM_005639.3	c.1103T>C	p.Ile368Thr	missense_variant	Exon 11 of 11	ENST00000261205.9	NP_005630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYT1	ENST00000261205.9	c.1103T>C	p.Ile368Thr	missense_variant	Exon 11 of 11	1	NM_005639.3	ENSP00000261205.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome Pathogenic:3

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Dec 12, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 18, 2019

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Likely pathogenic for Baker-Gordon syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6: Assumed de novo, but without confirmation of paternity and maternity. PS3-Moderate: Well-established functional studies show a deleterious effect (downgraded to Moderate). PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PS4-Supporting: Prevalence in affecteds statistically increased over controls (downgraded to Supporting). -

not provided Pathogenic:2

Jul 13, 2017

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jun 13, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1103T>C (p.I368T) alteration is located in exon 12 (coding exon 8) of the SYT1 gene. This alteration results from a T to C substitution at nucleotide position 1103, causing the isoleucine (I) at amino acid position 368 to be replaced by a threonine (T). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported de novo in multiple patients with neurodevelopmental disorders that included global developmental delay, intellectual disability, hypotonia, dyskinetic movements, and behavior disorder. Additional features included talipes and nystagmus or esotropia (Baker, 2015; Baker, 2018; Melland, 2022). This amino acid position is highly conserved in available vertebrate species. In vivo assessment of a child with a heterozygous I368T SYT1 mutation and in vitro investigation of the mutation in isolated mouse neurons showed abnormal kinetics of neurophysiological function (Baker, 2015). Using immunocytochemistry and electrophysiological recordings of synaptic currents in cultured mouse hippocampal and cortical neurons, Bradberry et. al. (2020) showed synaptic transmission was impaired in neurons expressing this mutant variant, demonstrating potent, graded dominant-negative effects. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

SYT1-associated neurodevelopmental disorder Pathogenic:1

Jul 01, 2018

Raymond Lab, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;D;.;D
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	.;.;D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	L;L;.;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.027	D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D
Polyphen		0.17	B;B;.;B
Vest4		0.63
MutPred		0.72		Loss of stability (P = 0.0107);Loss of stability (P = 0.0107);.;Loss of stability (P = 0.0107);
MVP		0.54
MPC		1.8
ClinPred		0.93	D
GERP RS		6.2
Varity_R		0.68
gMVP		0.78

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: rs1135402761; hg19: chr12-79842738;