chr11-7313699-C-G

Variant names:

• chr11-7313699-C-G
• rs138467146
• NM_175733.4:c.802C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_175733.4(SYT9):​c.802C>G​(p.Arg268Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 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. R268W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SYT9 NM_175733.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33
• Publications: 0 publications found

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]

ACMG classification

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, 0.808

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175733.4. 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
	SYT9	NM_175733.4	MANE Select	c.802C>G	p.Arg268Gly	missense	Exon 3 of 7	NP_783860.1	Q86SS6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT9	ENST00000318881.11	TSL:1 MANE Select	c.802C>G	p.Arg268Gly	missense	Exon 3 of 7	ENSP00000324419.6	Q86SS6
	SYT9	ENST00000524820.6	TSL:2	n.706C>G		non_coding_transcript_exon	Exon 3 of 9	ENSP00000432141.2	E9PDN4
	SYT9	ENST00000532592.1	TSL:2	n.497+10309C>G		intron	N/A	ENSP00000434558.1	B3KNT7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.22	N
PhyloP100		3.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.46		Loss of solvent accessibility (P = 0.0044)
MVP		0.36
MPC		1.4
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.84
gMVP		0.68
Mutation Taster		=15/85	disease causing

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: rs138467146; hg19: chr11-7334930;