10-46580325-C-T

Variant names:

• chr10-46580325-C-T
• rs782702981
• NM_031912.5:c.169C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031912.5(SYT15):​c.169C>T​(p.Arg57Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R57Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000098 (0 hom., cov: 13)
  • Exomes 𝑓: 0.0000091 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYT15 NM_031912.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32
• Publications: 0 publications found

Genes affected

SYT15 (HGNC:17167): (synaptotagmin 15) This gene encodes a member of the Synaptotagmin (Syt) family of membrane trafficking proteins. Members of this family contain a transmembrane region and a C-terminal-type tandem C2 domain. Unlike related family members, the encoded protein may be involved in membrane trafficking in non-neuronal tissues. Two trancript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09618759).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031912.5. 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
	SYT15	NM_031912.5	MANE Select	c.169C>T	p.Arg57Trp	missense	Exon 2 of 8	NP_114118.2
	SYT15	NM_181519.3		c.169C>T	p.Arg57Trp	missense	Exon 2 of 9	NP_852660.1	Q9BQS2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYT15	ENST00000374321.9	TSL:2 MANE Select	c.169C>T	p.Arg57Trp	missense	Exon 2 of 8	ENSP00000363441.4	Q9BQS2-1
	SYT15	ENST00000503753.5	TSL:1	c.169C>T	p.Arg57Trp	missense	Exon 2 of 9	ENSP00000427607.1	Q9BQS2-2
	SYT15	ENST00000374323.8	TSL:2	c.372-569C>T		intron	N/A	ENSP00000363443.3

Frequencies

GnomAD3 genomes AF: 0.00000981 AC: 1 AN: 101934 Hom.: 0 Cov.: 13

Gnomad AFR AF: 0.0000475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000805 AC: 20 AN: 248584 AF XY: 0.0000667

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000910 AC: 5 AN: 549184 Hom.: 0 Cov.: 7 AF XY: 0.00000358 AC XY: 1 AN XY: 279482

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11614

American (AMR) AF: 0.0000526 AC: 1 AN: 19002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13386

East Asian (EAS) AF: 0.00 AC: 0 AN: 29974

South Asian (SAS) AF: 0.0000255 AC: 1 AN: 39200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1942

European-Non Finnish (NFE) AF: 0.00000790 AC: 3 AN: 379598

Other (OTH) AF: 0.00 AC: 0 AN: 27700

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000145500), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000981 AC: 1 AN: 101934 Hom.: 0 Cov.: 13 AF XY: 0.0000207 AC XY: 1 AN XY: 48376

African (AFR) AF: 0.0000475 AC: 1 AN: 21036

American (AMR) AF: 0.00 AC: 0 AN: 10368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2718

East Asian (EAS) AF: 0.00 AC: 0 AN: 3836

South Asian (SAS) AF: 0.00 AC: 0 AN: 2792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51894

Other (OTH) AF: 0.00 AC: 0 AN: 1326

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_noAF	Benign	-0.80
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.096	T
PhyloP100		1.3
PROVEAN	Benign	-0.16	N
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.015	D
Vest4		0.14
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs782702981; hg19: chr10-46969292;