12-33376853-G-T

Variant names:

• chr12-33376853-G-T
• rs200421519
• NM_198992.4:c.1549C>A

Variant summary

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

The NM_198992.4(SYT10):​c.1549C>A​(p.Pro517Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P517A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SYT10 NM_198992.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.19
• Publications: 0 publications found

Genes affected

SYT10 (HGNC:19266): (synaptotagmin 10) Predicted to enable several functions, including phospholipid binding activity; protein dimerization activity; and syntaxin binding activity. Predicted to be involved in several processes, including cellular response to calcium ion; regulation of secretion by cell; and sensory perception of smell. Predicted to be located in synapse and transport vesicle membrane. Predicted to be integral component of membrane. Predicted to be active in exocytic vesicle and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198992.4. 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
	SYT10	NM_198992.4	MANE Select	c.1549C>A	p.Pro517Thr	missense	Exon 7 of 7	NP_945343.1	Q6XYQ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT10	ENST00000228567.7	TSL:1 MANE Select	c.1549C>A	p.Pro517Thr	missense	Exon 7 of 7	ENSP00000228567.3	Q6XYQ8
	SYT10	ENST00000539102.1	TSL:1	n.*1144C>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000444577.1	F5GZB8
	SYT10	ENST00000539102.1	TSL:1	n.*1144C>A		3_prime_UTR	Exon 9 of 9	ENSP00000444577.1	F5GZB8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Benign	0.14	T
Sift4G	Benign	0.15	T
Polyphen		0.10	B
Vest4		0.63
MutPred		0.36		Gain of catalytic residue at P519 (P = 0.0011)
MVP		0.57
MPC		0.68
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.16
gMVP		0.54
Mutation Taster		=50/50

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: rs200421519; hg19: chr12-33529788;