NM_005639.3:c.5T>C

Variant names:

• chr12-79217524-T-C
• rs773799671
• NM_005639.3:c.5T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BS1_Supporting BS2

The NM_005639.3(SYT1):​c.5T>C​(p.Val2Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000418 in 1,434,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: SYT1 NM_005639.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44
• 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: Likely_benign. The variant received -6 ACMG points.

• 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=0.20178655).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000418 (6/1434620) while in subpopulation AMR AF = 0.000149 (6/40210). AF 95% confidence interval is 0.0000644. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 6 AD gene.

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.5T>C	p.Val2Ala	missense	Exon 4 of 11	NP_005630.1	P21579
	SYT1	NM_001135805.2		c.5T>C	p.Val2Ala	missense	Exon 5 of 12	NP_001129277.1	P21579
	SYT1	NM_001135806.2		c.5T>C	p.Val2Ala	missense	Exon 3 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.5T>C	p.Val2Ala	missense	Exon 4 of 11	ENSP00000261205.4	P21579
	SYT1	ENST00000393240.7	TSL:1	c.5T>C	p.Val2Ala	missense	Exon 5 of 12	ENSP00000376932.3	P21579
	SYT1	ENST00000552744.5	TSL:1	c.5T>C	p.Val2Ala	missense	Exon 3 of 10	ENSP00000447575.1	P21579

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000265 AC: 6 AN: 226490 AF XY: 0.00000809

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000418 AC: 6 AN: 1434620 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 713876

African (AFR) AF: 0.00 AC: 0 AN: 31784

American (AMR) AF: 0.000149 AC: 6 AN: 40210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25208

East Asian (EAS) AF: 0.00 AC: 0 AN: 38450

South Asian (SAS) AF: 0.00 AC: 0 AN: 83200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100908

Other (OTH) AF: 0.00 AC: 0 AN: 59258

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.025
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.061
Sift	Benign	0.071	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.16		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.17
MPC		0.29
ClinPred		0.16	T
GERP RS		5.5
Varity_R		0.049
gMVP		0.42
Mutation Taster		=84/16	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: rs773799671; hg19: chr12-79611304;