NM_020783.4:c.494T>A

Variant names:

• chr18-43273935-A-T
• rs141781369
• NM_020783.4:c.494T>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 13/22 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.04
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -16 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 VariationId is 790738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020783.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT4	NM_020783.4	MANE Select	c.494T>A	p.Phe165Tyr	missense	Exon 2 of 4	NP_065834.1	Q9H2B2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT4	ENST00000255224.8	TSL:1 MANE Select	c.494T>A	p.Phe165Tyr	missense	Exon 2 of 4	ENSP00000255224.2	Q9H2B2-1
	SYT4	ENST00000585604.1	TSL:1	n.158-2103T>A		intron	N/A
	SYT4	ENST00000967898.1		c.494T>A	p.Phe165Tyr	missense	Exon 2 of 4	ENSP00000637957.1

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

GnomAD2 exomes AF: 0.000810 AC: 203 AN: 250548 AF XY: 0.000975

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 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

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000895 AC: 4 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00357 AC: 308 AN: 86248

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53402

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.000648 AC: 721 AN: 1111928

Other (OTH) AF: 0.00113 AC: 68 AN: 60386

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

African (AFR) AF: 0.000120 AC: 5 AN: 41560

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.12
Sift	Benign	0.35	T
Sift4G	Benign	0.53	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
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

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