chr6-158665559-G-A

Variant names:

• chr6-158665559-G-A
• rs760246645
• NM_001242394.2:c.275G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001242394.2(SYTL3):​c.275G>A​(p.Arg92Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000885 in 1,581,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: SYTL3 NM_001242394.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYTL3	NM_001242394.2	c.275G>A	p.Arg92Gln	missense_variant	Exon 5 of 18	ENST00000611299.5	NP_001229323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYTL3	ENST00000611299.5	c.275G>A	p.Arg92Gln	missense_variant	Exon 5 of 18	5	NM_001242394.2	ENSP00000483936.1
SYTL3	ENST00000360448.8	c.275G>A	p.Arg92Gln	missense_variant	Exon 6 of 19	5		ENSP00000353631.4
SYTL3	ENST00000367081.7	c.275G>A	p.Arg92Gln	missense_variant	Exon 5 of 16	5		ENSP00000356048.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000154 AC: 3 AN: 194424 AF XY: 0.00000963

Gnomad AFR exome AF: 0.000163

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000119

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000630 AC: 9 AN: 1429424 Hom.: 0 Cov.: 31 AF XY: 0.00000848 AC XY: 6 AN XY: 707566

African (AFR) AF: 0.0000903 AC: 3 AN: 33214

American (AMR) AF: 0.00 AC: 0 AN: 38022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.00 AC: 0 AN: 38622

South Asian (SAS) AF: 0.00 AC: 0 AN: 81518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00000456 AC: 5 AN: 1096650

Other (OTH) AF: 0.0000169 AC: 1 AN: 59252

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

African (AFR) AF: 0.000121 AC: 5 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000251 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.275G>A (p.R92Q) alteration is located in exon 5 (coding exon 2) of the SYTL3 gene. This alteration results from a G to A substitution at nucleotide position 275, causing the arginine (R) at amino acid position 92 to be replaced by a glutamine (Q). 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	0.11
BayesDel_addAF	Benign	-0.0027	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	.;T;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;.;D;.
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.5	M;M;M;M
PhyloP100		6.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	.;D;.;D
REVEL	Uncertain	0.56
Sift	Benign	0.049	.;D;.;T
Sift4G	Benign	0.092	T;T;T;T
Polyphen		0.99	D;D;D;D
Vest4		0.47
MutPred		0.87		Loss of MoRF binding (P = 0.0121);Loss of MoRF binding (P = 0.0121);Loss of MoRF binding (P = 0.0121);Loss of MoRF binding (P = 0.0121);
MVP		0.58
MPC		0.10
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.21
gMVP		0.48
Mutation Taster		=273/27	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: rs760246645; hg19: chr6-159086591;