18-43270363-C-A

Position:

• chr18-43270363-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020783.4(SYT4):​c.1256G>T​(p.Trp419Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYT4 NM_020783.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYT4	NM_020783.4	c.1256G>T	p.Trp419Leu	missense_variant	4/4	ENST00000255224.8	NP_065834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYT4	ENST00000255224.8	c.1256G>T	p.Trp419Leu	missense_variant	4/4	1	NM_020783.4	ENSP00000255224.2
SYT4	ENST00000585604.1	n.564G>T		non_coding_transcript_exon_variant	3/3	1
SYT4	ENST00000590752.5	c.1202G>T	p.Trp401Leu	missense_variant	4/4	2		ENSP00000466930.1
SYT4	ENST00000586678.1	n.446G>T		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Mar 19, 2024

The c.1256G>T (p.W419L) alteration is located in exon 4 (coding exon 4) of the SYT4 gene. This alteration results from a G to T substitution at nucleotide position 1256, causing the tryptophan (W) at amino acid position 419 to be replaced by a leucine (L). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-11	D;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.92		Loss of MoRF binding (P = 0.0148);.;
MVP		0.94
MPC		0.68
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-40850328; COSMIC: COSV105042919; COSMIC: COSV105042919;