18-43273924-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_020783.4(SYT4):c.505G>A(p.Ala169Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00099 in 1,614,044 control chromosomes in the GnomAD database, including 27 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00085 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (25 hom.)
• Consequence: SYT4 NM_020783.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.21

Genes affected

SYT4 (HGNC:11512): (synaptotagmin 4) Predicted to enable several functions, including calcium ion binding activity; phospholipid binding activity; and syntaxin binding activity. Involved in negative regulation of catecholamine secretion and positive regulation of dendrite extension. Predicted to be located in several cellular components, including microvesicle; perinuclear region of cytoplasm; and secretory vesicle. Predicted to be active in several cellular components, including axon; exocytic vesicle; and glutamatergic synapse. Predicted to be integral component of neuronal dense core vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007933378).
• BP6: Variant 18-43273924-C-T is Benign according to our data. Variant chr18-43273924-C-T is described in ClinVar as [Benign]. Clinvar id is 723190.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYT4	NM_020783.4	c.505G>A	p.Ala169Thr	missense_variant	2/4	ENST00000255224.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYT4	ENST00000255224.8	c.505G>A	p.Ala169Thr	missense_variant	2/4	1	NM_020783.4	P1

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152182 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00202 AC: 506 AN: 250640 Hom.: 11 AF XY: 0.00255 AC XY: 345 AN XY: 135450

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00100 AC: 1468 AN: 1461744 Hom.: 25 Cov.: 31 AF XY: 0.00137 AC XY: 993 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152300 Hom.: 2 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000506 Hom.: 0

Bravo AF: 0.000722

ExAC AF: 0.00224 AC: 272

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.47	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Benign	0.12
Sift	Benign	0.088	T;.
Sift4G	Benign	0.20	T;T
Polyphen		0.76	P;.
Vest4		0.25
MVP		0.34
MPC		0.27
ClinPred		0.034	T
GERP RS		3.2
Varity_R		0.23
gMVP		0.59

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: rs200418581; hg19: chr18-40853889; COSMIC: COSV54899854; COSMIC: COSV54899854;