6-158663377-C-T

Position:

• chr6-158663377-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001242394.2(SYTL3):​c.109C>T​(p.Arg37Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SYTL3 NM_001242394.2 missense, splice_region
• Scores: Splicing: ADA: 0.6383
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89

Genes affected

SYTL3 (HGNC:15587): (synaptotagmin like 3) The protein encoded by this gene belongs to a family of peripheral membrane proteins that play a role in vesicular trafficking. This protein binds phospholipids in the presence of calcium ions. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31117192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYTL3	NM_001242394.2	c.109C>T	p.Arg37Trp	missense_variant, splice_region_variant	4/18	ENST00000611299.5	NP_001229323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYTL3	ENST00000611299.5	c.109C>T	p.Arg37Trp	missense_variant, splice_region_variant	4/18	5	NM_001242394.2	ENSP00000483936	P1
SYTL3	ENST00000360448.8	c.109C>T	p.Arg37Trp	missense_variant, splice_region_variant	5/19	5		ENSP00000353631	P1
SYTL3	ENST00000367081.7	c.109C>T	p.Arg37Trp	missense_variant, splice_region_variant	4/16	5		ENSP00000356048

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250848 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135590

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000871

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461058 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 726816

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74278

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000479

Bravo AF: 0.000121

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.109C>T (p.R37W) alteration is located in exon 4 (coding exon 1) of the SYTL3 gene. This alteration results from a C to T substitution at nucleotide position 109, causing the arginine (R) at amino acid position 37 to be replaced by a tryptophan (W). 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	0.13
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	.;D;D;D
Eigen	Benign	0.016
Eigen_PC	Benign	0.067
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.86	D;.;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.3	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.3	.;D;.;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	.;D;.;D
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		0.094	B;B;B;B
Vest4		0.43
MutPred		0.40		Loss of disorder (P = 0.0121);Loss of disorder (P = 0.0121);Loss of disorder (P = 0.0121);Loss of disorder (P = 0.0121);
MVP		0.64
MPC		0.017
ClinPred		0.91	D
GERP RS		3.4
Varity_R		0.41
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.64
dbscSNV1_RF	Benign	0.40
SpliceAI score (max)		0.020		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: rs762716551; hg19: chr6-159084409;