Genetic Variant SYTL4:p.Glu524Lys (chrX-100679401-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001370165.1(SYTL4):c.1570G>A(p.Glu524Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,205,157 control chromosomes in the GnomAD database, including 1 homozygotes. There are 107 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.00027 ( 1 hom. 103 hem. )

Consequence

SYTL4
NM_001370165.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.34

Variant links:

Genes affected

SYTL4 (HGNC:15588): (synaptotagmin like 4) This gene encodes a member of the synaptotagmin like protein family. Members of this family are characterized by an N-terminal Rab27 binding domain and C-terminal tandem C2 domains. The encoded protein binds specific small Rab GTPases and is involved in intracellular membrane trafficking. This protein binds Rab27 and may be involved in inhibiting dense core vesicle exocytosis. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Mar 2010]

SYTL4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03453383).

BP6

Variant X-100679401-C-T is Benign according to our data. Variant chrX-100679401-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2661038.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYTL4	NM_001370165.1 link	c.1570G>A	p.Glu524Lys	missense_variant	Exon 18 of 20	ENST00000372989.6	NP_001357094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYTL4	ENST00000372989.6 link	c.1570G>A	p.Glu524Lys	missense_variant	Exon 18 of 20	1	NM_001370165.1	ENSP00000362080.1	Q96C24-1
SYTL4	ENST00000276141.10 link	c.1570G>A	p.Glu524Lys	missense_variant	Exon 15 of 17	1		ENSP00000276141.6	Q96C24-1
SYTL4	ENST00000263033.9 link	c.1570G>A	p.Glu524Lys	missense_variant	Exon 15 of 17	2		ENSP00000263033.5	Q96C24-1
SYTL4	ENST00000685623.1 link	c.1570G>A	p.Glu524Lys	missense_variant	Exon 18 of 20			ENSP00000509693.1	Q96C24-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

111631

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33797

show subpopulations

Gnomad AFR

AF:

0.0000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000953

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000328

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.000226

Gnomad OTH

AF:

0.00266

GnomAD3 exomes

AF:

0.000312

AC:

AN:

182767

Hom.:

AF XY:

0.000312

AC XY:

AN XY:

67241

show subpopulations

Gnomad AFR exome

AF:

0.0000761

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000317

Gnomad FIN exome

AF:

0.000250

Gnomad NFE exome

AF:

0.000502

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000267

AC:

292

AN:

1093471

Hom.:

Cov.:

AF XY:

0.000287

AC XY:

103

AN XY:

358957

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000296

Gnomad4 FIN exome

AF:

0.000346

Gnomad4 NFE exome

AF:

0.000260

Gnomad4 OTH exome

AF:

0.000523

GnomAD4 genome

AF:

0.000197

AC:

AN:

111686

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33862

show subpopulations

Gnomad4 AFR

AF:

0.0000651

Gnomad4 AMR

AF:

0.0000951

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000328

Gnomad4 NFE

AF:

0.000226

Gnomad4 OTH

AF:

0.00263

Alfa

AF:

0.000443

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000832

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYTL4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

T;T;T

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.78

.;T;.

M_CAP

Benign

0.013

MetaRNN

Benign

0.035

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.25

N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.36

N;N;N

REVEL

Benign

0.050

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.94

T;T;T

Polyphen

0.049

B;B;B

Vest4

0.14

MVP

0.20

ClinPred

0.014

GERP RS

4.0

Varity_R

0.21

gMVP

0.33

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over