rs144900171

Variant names:

• chr12-79448968-C-G
• rs144900171
• NM_005639.3:c.1113C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-79448968-C-G
• chr12-79448968-C-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_005639.3(SYT1):​c.1113C>G​(p.Asn371Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N371N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYT1 NM_005639.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.123
• Publications: 9 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: Pathogenic. The variant received 14 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, 7 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, 0.781
• PP5: Variant 12-79448968-C-G is Pathogenic according to our data. Variant chr12-79448968-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 590281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYT1	NM_005639.3	c.1113C>G	p.Asn371Lys	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.1113C>G	p.Asn371Lys	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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome Pathogenic:2

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. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. -

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	1.0
BayesDel_addAF	Benign	-0.0039	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D;.;D
Eigen	Benign	0.17
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.59	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	2.0	M;M;.;M
PhyloP100		-0.12
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.76
MutPred		0.71		Gain of catalytic residue at K376 (P = 0.0014);Gain of catalytic residue at K376 (P = 0.0014);.;Gain of catalytic residue at K376 (P = 0.0014);
MVP		0.68
MPC		2.8
ClinPred		0.96	D
GERP RS		2.3
Varity_R		0.87
gMVP		0.85
Mutation Taster		=1/99	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: rs144900171; hg19: chr12-79842748;