18-43273616-C-G

Variant names:

• chr18-43273616-C-G
• NM_020783.4:c.813G>C
• SYT4 p.Met271Ile

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020783.4(SYT4):​c.813G>C​(p.Met271Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYT4 NM_020783.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.923
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22584295).

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.813G>C	p.Met271Ile	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.813G>C	p.Met271Ile	missense	Exon 2 of 4	ENSP00000255224.2	Q9H2B2-1
	SYT4	ENST00000585604.1	TSL:1	n.158-1784G>C		intron	N/A
	SYT4	ENST00000596867.1	TSL:5	c.3G>C	p.Met1?	start_lost	Exon 2 of 4	ENSP00000470516.1	M0QZF3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.92
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.090
Sift	Benign	0.17	T
Sift4G	Benign	0.17	T
Varity_R		0.25
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr18-40853581;