11-7420507-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175733.4(SYT9):c.1339G>A(p.Val447Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,614,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (1 hom.)
• Consequence: SYT9 NM_175733.4 missense, splice_region
• Scores: Splicing: ADA: 0.006495
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.14

Genes affected

SYT9 (HGNC:19265): (synaptotagmin 9) Predicted to enable several functions, including calcium ion binding activity; phospholipid binding activity; and syntaxin binding activity. Predicted to be involved in calcium-ion regulated exocytosis; cellular response to calcium ion; and regulation of secretion by cell. Predicted to be located in clathrin-coated endocytic vesicle membrane. Predicted to be active in hippocampal mossy fiber to CA3 synapse; plasma membrane; and secretory vesicle. Predicted to be integral component of synaptic vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

SYT9-AS1 (HGNC:56173): (SYT9 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09236118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYT9	NM_175733.4	c.1339G>A	p.Val447Ile	missense_variant, splice_region_variant	6/7	ENST00000318881.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYT9	ENST00000318881.11	c.1339G>A	p.Val447Ile	missense_variant, splice_region_variant	6/7	1	NM_175733.4	P1
SYT9-AS1	ENST00000530201.2	n.1421-293C>T		intron_variant, non_coding_transcript_variant		3
SYT9	ENST00000524820.6	c.*436G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	7/9	2
SYT9	ENST00000532592.1	c.*270G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	5/6	2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000677 AC: 17 AN: 251282 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461836 Hom.: 1 Cov.: 31 AF XY: 0.0000564 AC XY: 41 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.000123 AC: 15

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

Dec 13, 2022

The c.1339G>A (p.V447I) alteration is located in exon 6 (coding exon 6) of the SYT9 gene. This alteration results from a G to A substitution at nucleotide position 1339, causing the valine (V) at amino acid position 447 to be replaced by an isoleucine (I). 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	Benign	0.25
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	23
Dann	Benign	0.97
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.089
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.64	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.21
Sift	Benign	0.67	T
Sift4G	Benign	1.0	T
Polyphen		0.34	B
Vest4		0.16
MutPred		0.35		Gain of catalytic residue at M442 (P = 0.0312);
MVP		0.78
MPC		0.77
ClinPred		0.19	T
GERP RS		4.7
Varity_R		0.091
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0065
dbscSNV1_RF	Benign	0.19
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: rs571404172; hg19: chr11-7441738;