chr6-158665606-G-C

Variant names:

• chr6-158665606-G-C
• rs751441226
• NM_001242394.2:c.322G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001242394.2(SYTL3):​c.322G>C​(p.Glu108Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000898 in 1,559,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: SYTL3 NM_001242394.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.23
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39004365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYTL3	NM_001242394.2	c.322G>C	p.Glu108Gln	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.322G>C	p.Glu108Gln	missense_variant	Exon 5 of 18	5	NM_001242394.2	ENSP00000483936.1
SYTL3	ENST00000360448.8	c.322G>C	p.Glu108Gln	missense_variant	Exon 6 of 19	5		ENSP00000353631.4
SYTL3	ENST00000367081.7	c.322G>C	p.Glu108Gln	missense_variant	Exon 5 of 16	5		ENSP00000356048.4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000293 AC: 5 AN: 170480 AF XY: 0.0000333

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000735

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000853 AC: 12 AN: 1407140 Hom.: 0 Cov.: 31 AF XY: 0.0000115 AC XY: 8 AN XY: 693742

African (AFR) AF: 0.00 AC: 0 AN: 32774

American (AMR) AF: 0.000111 AC: 4 AN: 35966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24972

East Asian (EAS) AF: 0.0000530 AC: 2 AN: 37750

South Asian (SAS) AF: 0.00 AC: 0 AN: 80004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4924

European-Non Finnish (NFE) AF: 0.00000554 AC: 6 AN: 1082310

Other (OTH) AF: 0.00 AC: 0 AN: 58282

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74228

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000253 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.322G>C (p.E108Q) alteration is located in exon 5 (coding exon 2) of the SYTL3 gene. This alteration results from a G to C substitution at nucleotide position 322, causing the glutamic acid (E) at amino acid position 108 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	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T;T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;.
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	-0.038	T
MutationAssessor	Uncertain	2.2	M;M;M;M
PhyloP100		9.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.59	.;N;.;N
REVEL	Uncertain	0.42
Sift	Benign	0.059	.;T;.;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		1.0	D;P;P;P
Vest4		0.42
MutPred		0.42		Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);
MVP		0.62
MPC		0.025
ClinPred		0.22	T
GERP RS		5.8
Varity_R		0.14
gMVP		0.33
Mutation Taster		=217/83	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: rs751441226; hg19: chr6-159086638;