18-43273935-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_020783.4(SYT4):c.494T>A(p.Phe165Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000765 in 1,614,002 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (7 hom.)
• Consequence: SYT4 NM_020783.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.04

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009347409).
• BP6: Variant 18-43273935-A-T is Benign according to our data. Variant chr18-43273935-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 790738.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYT4	NM_020783.4	c.494T>A	p.Phe165Tyr	missense_variant	2/4	ENST00000255224.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYT4	ENST00000255224.8	c.494T>A	p.Phe165Tyr	missense_variant	2/4	1	NM_020783.4	P1

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000810 AC: 203 AN: 250548 Hom.: 1 AF XY: 0.000975 AC XY: 132 AN XY: 135396

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00330

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000743

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000800 AC: 1169 AN: 1461730 Hom.: 7 Cov.: 31 AF XY: 0.000905 AC XY: 658 AN XY: 727148

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00357

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000648

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74462

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000800 Hom.: 0

Bravo AF: 0.000385

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000799 AC: 97

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000889

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.0093	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.50	N;.
REVEL	Benign	0.12
Sift	Benign	0.35	T;.
Sift4G	Benign	0.53	T;T
Polyphen		0.80	P;.
Vest4		0.47
MVP		0.50
MPC		0.16
ClinPred		0.043	T
GERP RS		5.9
Varity_R		0.15
gMVP		0.33

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: rs141781369; hg19: chr18-40853900; COSMIC: COSV105838940; COSMIC: COSV105838940;