Genetic Variant SYTL4:p.Arg451Pro (chrX-100686087-C-G) – 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_001370165.1(SYTL4):c.1352G>C(p.Arg451Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,582 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. R451H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

SYTL4
NM_001370165.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.38

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

retinal disorder
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

SYTL4 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, 0.947

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370165.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYTL4	NM_001370165.1	MANE Select	c.1352G>C	p.Arg451Pro	missense	Exon 16 of 20	NP_001357094.1	Q96C24-1
SYTL4	NM_001370162.1		c.1352G>C	p.Arg451Pro	missense	Exon 14 of 19	NP_001357091.1
SYTL4	NM_001129896.3		c.1352G>C	p.Arg451Pro	missense	Exon 14 of 18	NP_001123368.1	Q96C24-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYTL4	ENST00000372989.6	TSL:1 MANE Select	c.1352G>C	p.Arg451Pro	missense	Exon 16 of 20	ENSP00000362080.1	Q96C24-1
SYTL4	ENST00000276141.10	TSL:1	c.1352G>C	p.Arg451Pro	missense	Exon 13 of 17	ENSP00000276141.6	Q96C24-1
SYTL4	ENST00000263033.9	TSL:2	c.1352G>C	p.Arg451Pro	missense	Exon 13 of 17	ENSP00000263033.5	Q96C24-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096582

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26387

American (AMR)

AF:

0.00

AC:

AN:

35123

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19359

East Asian (EAS)

AF:

0.00

AC:

AN:

30165

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40461

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841267

Other (OTH)

AF:

0.00

AC:

AN:

46040

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.95

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

2.9

PhyloP100

7.4

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.45

Sift

Uncertain

0.0020

Sift4G

Benign

0.090

Polyphen

1.0

Vest4

0.88

MutPred

0.71

Loss of catalytic residue at R451 (P = 0.0104)

MVP

0.42

ClinPred

1.0

GERP RS

5.9

Varity_R

0.99

gMVP

0.80

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over