12-79448945-G-A

Variant names:

• chr12-79448945-G-A
• rs1555226395
• NM_005639.3:c.1090G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_005639.3(SYT1):​c.1090G>A​(p.Asp364Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D364Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYT1 NM_005639.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.99
• Publications: 1 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: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000257894 (HGNC:58105):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 12-79448945-G-A is Pathogenic according to our data. Variant chr12-79448945-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521149.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT1	NM_005639.3	MANE Select	c.1090G>A	p.Asp364Asn	missense	Exon 11 of 11	NP_005630.1
	SYT1	NM_001135805.2		c.1090G>A	p.Asp364Asn	missense	Exon 12 of 12	NP_001129277.1
	SYT1	NM_001135806.2		c.1090G>A	p.Asp364Asn	missense	Exon 10 of 10	NP_001129278.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT1	ENST00000261205.9	TSL:1 MANE Select	c.1090G>A	p.Asp364Asn	missense	Exon 11 of 11	ENSP00000261205.4
	SYT1	ENST00000393240.7	TSL:1	c.1090G>A	p.Asp364Asn	missense	Exon 12 of 12	ENSP00000376932.3
	SYT1	ENST00000552744.5	TSL:1	c.1090G>A	p.Asp364Asn	missense	Exon 10 of 10	ENSP00000447575.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jul 02, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		10
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.79		Gain of methylation at K367 (P = 0.0955)
MVP		0.79
MPC		2.6
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.93
gMVP		0.88
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555226395; hg19: chr12-79842725;