11-45246508-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020826.3(SYT13):c.851C>A(p.Pro284Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,613,894 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000074 (1 hom.)
• Consequence: SYT13 NM_020826.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.404

Genes affected

SYT13 (HGNC:14962): (synaptotagmin 13) This gene encodes a member of the large synaptotagmin protein family. Family members have an extracellular N-terminal transmembrane domain and a cytoplasmic C terminus with two tandem C2 domains (C2A and C2B). Synaptotogmin family members can form homo- and heteromeric complexes with each other. They also have different biochemical properties and developmental profiles, and patterns of tissue distribution. Synaptotagmins function as membrane traffickers in multicellular organisms. Two alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06392765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYT13	NM_020826.3	c.851C>A	p.Pro284Gln	missense_variant	5/6	ENST00000020926.8
SYT13	NM_001247987.2	c.419C>A	p.Pro140Gln	missense_variant	7/8
SYT13	XM_047427338.1	c.419C>A	p.Pro140Gln	missense_variant	5/6
SYT13	XM_047427339.1	c.419C>A	p.Pro140Gln	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYT13	ENST00000020926.8	c.851C>A	p.Pro284Gln	missense_variant	5/6	1	NM_020826.3	P1
SYT13	ENST00000533332.1	c.*868C>A		3_prime_UTR_variant, NMD_transcript_variant	7/8	1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000997 AC: 25 AN: 250756 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135522

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000739 AC: 108 AN: 1461722 Hom.: 1 Cov.: 31 AF XY: 0.0000853 AC XY: 62 AN XY: 727146

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000630

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000973 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.851C>A (p.P284Q) alteration is located in exon 5 (coding exon 5) of the SYT13 gene. This alteration results from a C to A substitution at nucleotide position 851, causing the proline (P) at amino acid position 284 to be replaced by a glutamine (Q). 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	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.019
Sift	Benign	0.14	T
Sift4G	Benign	0.066	T
Polyphen		0.11	B
Vest4		0.29
MVP		0.26
MPC		0.32
ClinPred		0.023	T
GERP RS		3.0
Varity_R		0.073
gMVP		0.36

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

Other links and lift over

dbSNP: rs762541247; hg19: chr11-45268059;