NM_003180.3:c.595G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_003180.3(SYT5):​c.595G>T​(p.Asp199Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000691 in 1,592,498 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

SYT5
NM_003180.3 missense

Scores

10
7
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.08
Variant links:
Genes affected
SYT5 (HGNC:11513): (synaptotagmin 5) Synaptotagmins, such as SYT5, are a family of type III membrane proteins characterized by cytoplasmic repeats related to protein kinase C (see MIM 176960) regulatory (C2) domains, which are thought to bind calcium. Synaptotagmins may act both as negative regulators of vesicle fusion, allowing fusion in the presence of calcium, and as calcium receptors or sensor molecules (summary by Hudson and Birnbaum, 1995 [PubMed 7597049]).[supplied by OMIM, Feb 2011]
DNAAF3-AS1 (HGNC:55292): (DNAAF3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a binding_site (size 0) in uniprot entity SYT5_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYT5NM_003180.3 linkc.595G>T p.Asp199Tyr missense_variant Exon 6 of 9 ENST00000354308.8 NP_003171.2 O00445-1A0A024R4N8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYT5ENST00000354308.8 linkc.595G>T p.Asp199Tyr missense_variant Exon 6 of 9 1 NM_003180.3 ENSP00000346265.2 O00445-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152130
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000694
AC:
10
AN:
1440368
Hom.:
0
Cov.:
32
AF XY:
0.00000699
AC XY:
5
AN XY:
715812
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:
0.0000121
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000816
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152130
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 04, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.595G>T (p.D199Y) alteration is located in exon 6 (coding exon 5) of the SYT5 gene. This alteration results from a G to T substitution at nucleotide position 595, causing the aspartic acid (D) at amino acid position 199 to be replaced by a tyrosine (Y). 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
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
.;D;D
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.96
D;.;D
M_CAP
Uncertain
0.085
D
MetaRNN
Pathogenic
0.94
D;D;D
MetaSVM
Benign
-0.46
T
MutationAssessor
Pathogenic
4.0
.;H;H
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-8.7
.;D;D
REVEL
Uncertain
0.53
Sift
Pathogenic
0.0
.;D;D
Sift4G
Uncertain
0.0090
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.93
MutPred
0.83
.;Gain of MoRF binding (P = 0.0691);Gain of MoRF binding (P = 0.0691);
MVP
0.45
MPC
1.9
ClinPred
1.0
D
GERP RS
4.3
Varity_R
0.95
gMVP
0.94

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.

Other links and lift over

dbSNP: rs1438134925; hg19: chr19-55686653; API