12-79292061-A-C

Position:

• chr12-79292061-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 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

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.13400048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYT1	NM_005639.3	c.405A>C	p.Glu135Asp	missense_variant	6/11	ENST00000261205.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYT1	ENST00000261205.9	c.405A>C	p.Glu135Asp	missense_variant	6/11	1	NM_005639.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 29, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

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;T;.;T;T;T
Eigen	Benign	-0.016
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	.;.;T;T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.84	L;L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Benign	0.073
Sift	Benign	0.068	T;T;T;T;D;D
Sift4G	Benign	0.20	T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;.
Vest4		0.17
MutPred		0.31		Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);.;Loss of loop (P = 0.0128);.;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

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: rs1879614972; hg19: chr12-79685841;