Genetic Variant SYTL3:p.Cys80Arg (chr6-158665522-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001242394.2(SYTL3):c.238T>C(p.Cys80Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,018 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: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SYTL3
NM_001242394.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.37

Publications

0 publications found

Variant links:

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]

SYTL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYTL3	NM_001242394.2 link	c.238T>C	p.Cys80Arg	missense_variant	Exon 5 of 18	ENST00000611299.5	NP_001229323.1	Q4VX76-1B4E2A9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYTL3	ENST00000611299.5 link	c.238T>C	p.Cys80Arg	missense_variant	Exon 5 of 18	5	NM_001242394.2	ENSP00000483936.1	Q4VX76-1
SYTL3	ENST00000360448.8 link	c.238T>C	p.Cys80Arg	missense_variant	Exon 6 of 19	5		ENSP00000353631.4	Q4VX76-1
SYTL3	ENST00000367081.7 link	c.238T>C	p.Cys80Arg	missense_variant	Exon 5 of 16	5		ENSP00000356048.4	Q4VX76-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1440018

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33290

American (AMR)

AF:

0.00

AC:

AN:

40254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25544

East Asian (EAS)

AF:

0.00

AC:

AN:

38930

South Asian (SAS)

AF:

0.00

AC:

AN:

82788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102206

Other (OTH)

AF:

0.00

AC:

AN:

59616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.238T>C (p.C80R) alteration is located in exon 5 (coding exon 2) of the SYTL3 gene. This alteration results from a T to C substitution at nucleotide position 238, causing the cysteine (C) at amino acid position 80 to be replaced by an arginine (R). 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

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;D;D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;.;T;.

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.5

H;H;H;H

PhyloP100

7.4

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-10

.;D;.;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.82

MutPred

0.75

Gain of MoRF binding (P = 0.003);Gain of MoRF binding (P = 0.003);Gain of MoRF binding (P = 0.003);Gain of MoRF binding (P = 0.003);

MVP

0.73

MPC

0.15

ClinPred

1.0

GERP RS

5.8

Varity_R

0.96

gMVP

0.83

Mutation Taster

=139/161

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over