dbSNP rs978828343: SYT4:p.Arg288Leu (chr18-43271819-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_020783.4(SYT4):c.863G>T(p.Arg288Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R288Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SYT4
NM_020783.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.63

Publications

1 publications found

Variant links:

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]

SYT4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.753

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.863G>T	p.Arg288Leu	missense	Exon 3 of 4	NP_065834.1	Q9H2B2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYT4	ENST00000255224.8	TSL:1 MANE Select	c.863G>T	p.Arg288Leu	missense	Exon 3 of 4	ENSP00000255224.2	Q9H2B2-1
SYT4	ENST00000585604.1	TSL:1	n.171G>T		non_coding_transcript_exon	Exon 2 of 3
SYT4	ENST00000967898.1		c.860G>T	p.Arg287Leu	missense	Exon 3 of 4	ENSP00000637957.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459784

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33416

American (AMR)

AF:

0.00

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39592

South Asian (SAS)

AF:

0.00

AC:

AN:

86096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110554

Other (OTH)

AF:

0.0000166

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.32

MutationAssessor

Uncertain

2.6

PhyloP100

7.6

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0010

Sift4G

Benign

0.11

Polyphen

0.99

Vest4

0.82

MutPred

0.50

Loss of MoRF binding (P = 0.0203)

MVP

0.92

MPC

0.26

ClinPred

0.99

GERP RS

5.5

Varity_R

0.64

gMVP

0.68

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over