chr12-79448968-C-A

Variant names:

• chr12-79448968-C-A
• NM_005639.3:c.1113C>A
• SYT1 p.Asn371Lys

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1_Very_Strong PM1 PM2 PP2 PP3

The NM_005639.3(SYT1):​c.1113C>A​(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. 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: Not reported in ClinVar
• Conservation: PhyloP100: -0.123
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina, PanelApp Australia

SYT1-AS1 (HGNC:58105):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_005639.3 (SYT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

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.1113C>A	p.Asn371Lys	missense	Exon 11 of 11	NP_005630.1	P21579
	SYT1	NM_001135805.2		c.1113C>A	p.Asn371Lys	missense	Exon 12 of 12	NP_001129277.1	P21579
	SYT1	NM_001135806.2		c.1113C>A	p.Asn371Lys	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.1113C>A	p.Asn371Lys	missense	Exon 11 of 11	ENSP00000261205.4	P21579
	SYT1	ENST00000393240.7	TSL:1	c.1113C>A	p.Asn371Lys	missense	Exon 12 of 12	ENSP00000376932.3	P21579
	SYT1	ENST00000552744.5	TSL:1	c.1113C>A	p.Asn371Lys	missense	Exon 10 of 10	ENSP00000447575.1	P21579

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.17
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.57	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.12
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.87
gMVP		0.85
Mutation Taster		=1/99	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-79842748;