chrX-100686087-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 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. R451C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)
Exomes š‘“: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

SYTL4
NM_001370165.1 missense

Scores

6
8
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.38
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYTL4NM_001370165.1 linkc.1352G>C p.Arg451Pro missense_variant Exon 16 of 20 ENST00000372989.6 NP_001357094.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYTL4ENST00000372989.6 linkc.1352G>C p.Arg451Pro missense_variant Exon 16 of 20 1 NM_001370165.1 ENSP00000362080.1 Q96C24-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
9.12e-7
AC:
1
AN:
1096582
Hom.:
0
Cov.:
29
AF XY:
0.00000276
AC XY:
1
AN XY:
362032
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000186
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.63
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T;T;T
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.88
.;D;.
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Benign
-1.2
T
MutationAssessor
Pathogenic
2.9
M;M;M
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-6.0
D;D;D
REVEL
Uncertain
0.45
Sift
Uncertain
0.0020
D;D;D
Sift4G
Benign
0.090
T;T;T
Polyphen
1.0
D;D;D
Vest4
0.88
MutPred
0.71
Loss of catalytic residue at R451 (P = 0.0104);Loss of catalytic residue at R451 (P = 0.0104);Loss of catalytic residue at R451 (P = 0.0104);
MVP
0.42
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.99
gMVP
0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-99941084; API