Genetic Variant SYTL3:p.Arg92Pro (chr6-158665559-G-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.275G>C(p.Arg92Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R92Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SYTL3
NM_001242394.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.25

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, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYTL3	NM_001242394.2 link	c.275G>C	p.Arg92Pro	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.275G>C	p.Arg92Pro	missense_variant	Exon 5 of 18	5	NM_001242394.2	ENSP00000483936.1	Q4VX76-1
SYTL3	ENST00000360448.8 link	c.275G>C	p.Arg92Pro	missense_variant	Exon 6 of 19	5		ENSP00000353631.4	Q4VX76-1
SYTL3	ENST00000367081.7 link	c.275G>C	p.Arg92Pro	missense_variant	Exon 5 of 16	5		ENSP00000356048.4	Q4VX76-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

194424

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1429430

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707570

African (AFR)

AF:

0.00

AC:

AN:

33214

American (AMR)

AF:

0.00

AC:

AN:

38022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25330

East Asian (EAS)

AF:

0.00

AC:

AN:

38622

South Asian (SAS)

AF:

0.00

AC:

AN:

81520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096654

Other (OTH)

AF:

0.00

AC:

AN:

59252

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

.;D;D;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.86

D;.;D;.

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.3

M;M;M;M

PhyloP100

6.3

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.7

.;D;.;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0020

.;D;.;D

Sift4G

Uncertain

0.0090

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.92

MutPred

0.85

Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);

MVP

0.65

MPC

0.15

ClinPred

0.99

GERP RS

5.8

Varity_R

0.83

gMVP

0.79

Mutation Taster

=45/55

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

Computational scores

Splicing

Publications

Other links and lift over