NM_005639.3:c.1103T>C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000994935: Well-established functional studies show a deleterious effect (downgraded to Moderate)." and additional evidence is available in ClinVar.

• 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
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia, Ambry Genetics, G2P

SYT1-AS1 (HGNC:58105):

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000994935: Well-established functional studies show a deleterious effect (downgraded to Moderate).; SCV003620268: 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.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 431484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005639.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT1	NM_005639.3	MANE Select	c.1103T>C	p.Ile368Thr	missense	Exon 11 of 11	NP_005630.1	P21579
	SYT1	NM_001135805.2		c.1103T>C	p.Ile368Thr	missense	Exon 12 of 12	NP_001129277.1	P21579
	SYT1	NM_001135806.2		c.1103T>C	p.Ile368Thr	missense	Exon 10 of 10	NP_001129278.1	P21579

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT1	ENST00000261205.9	TSL:1 MANE Select	c.1103T>C	p.Ile368Thr	missense	Exon 11 of 11	ENSP00000261205.4	P21579
	SYT1	ENST00000393240.7	TSL:1	c.1103T>C	p.Ile368Thr	missense	Exon 12 of 12	ENSP00000376932.3	P21579
	SYT1	ENST00000552744.5	TSL:1	c.1103T>C	p.Ile368Thr	missense	Exon 10 of 10	ENSP00000447575.1	P21579

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome (3)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	SYT1-associated neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.039	D
Polyphen		0.17	B
Vest4		0.63
MutPred		0.72		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1135402761; hg19: chr12-79842738;