NM_005639.3:c.405A>C

Variant names:

• chr12-79292061-A-C
• rs1879614972
• NM_005639.3:c.405A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005639.3(SYT1):​c.405A>C​(p.Glu135Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E135G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYT1 NM_005639.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.692
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13400048).

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.405A>C	p.Glu135Asp	missense	Exon 6 of 11	NP_005630.1	P21579
	SYT1	NM_001135805.2		c.405A>C	p.Glu135Asp	missense	Exon 7 of 12	NP_001129277.1	P21579
	SYT1	NM_001135806.2		c.405A>C	p.Glu135Asp	missense	Exon 5 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.405A>C	p.Glu135Asp	missense	Exon 6 of 11	ENSP00000261205.4	P21579
	SYT1	ENST00000393240.7	TSL:1	c.405A>C	p.Glu135Asp	missense	Exon 7 of 12	ENSP00000376932.3	P21579
	SYT1	ENST00000552744.5	TSL:1	c.405A>C	p.Glu135Asp	missense	Exon 5 of 10	ENSP00000447575.1	P21579

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.016
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.84	L
PhyloP100		0.69
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.073
Sift	Benign	0.068	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.31		Loss of loop (P = 0.0128)
MVP		0.13
MPC		0.22
ClinPred		0.20	T
GERP RS		3.2
Varity_R		0.078
gMVP		0.099
Mutation Taster		=80/20	polymorphism

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: rs1879614972; hg19: chr12-79685841;