chr12-79217524-T-C

Position:

• chr12-79217524-T-C

Variant summary

Our verdict is Likely benign. Variant got -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. 12/21 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

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 Likely_benign. Variant got -6 ACMG points.

• 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=0.20178655).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome 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 gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYT1	NM_005639.3	c.5T>C	p.Val2Ala	missense_variant	4/11	ENST00000261205.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYT1	ENST00000261205.9	c.5T>C	p.Val2Ala	missense_variant	4/11	1	NM_005639.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000265 AC: 6 AN: 226490 Hom.: 0 AF XY: 0.00000809 AC XY: 1 AN XY: 123634

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000149

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2022

The c.5T>C (p.V2A) alteration is located in exon 5 (coding exon 1) of the SYT1 gene. This alteration results from a T to C substitution at nucleotide position 5, causing the valine (V) at amino acid position 2 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;.;T;T;T;T;T;T;T
Eigen	Benign	-0.025
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	.;.;T;T;T;.;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.2	L;L;.;.;.;.;.;L;.;.
MutationTaster	Benign	0.89	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.28	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.071	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.25	T;T;T;D;D;D;D;T;T;T
Polyphen		0.0	B;B;.;.;.;.;.;B;.;.
Vest4		0.20
MutPred		0.16		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);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

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: rs773799671; hg19: chr12-79611304;