dbSNP rs372086839: SYT8:p.Thr160Lys (chr11-1836247-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001394072.1(SYT8):c.479C>A(p.Thr160Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,604 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. T160M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SYT8
NM_001394072.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.89

Publications

0 publications found

Variant links:

Genes affected

SYT8 (HGNC:19264): (synaptotagmin 8) This gene encodes a member of the synaptotagmin protein family. Synaptotagmins are membrane proteins that are important in neurotransmission and hormone secretion, both of which involve regulated exocytosis. Expression of the encoded protein in human pancreatic islets has been connected to activity of the promoter for the insulin gene, on the same chromosome several hundred kilobases away (PMID: 21336277 and 22928559). This association would link response to gluclose to insulin secretion. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

SYT8 links:

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ACMG classification

Classification was made for transcript

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, 0.814

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394072.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYT8	NM_001394072.1	MANE Select	c.479C>A	p.Thr160Lys	missense	Exon 4 of 8	NP_001381001.1	Q8NBV8-4
SYT8	NM_001290332.2		c.524C>A	p.Thr175Lys	missense	Exon 5 of 9	NP_001277261.2
SYT8	NM_001290333.2		c.521C>A	p.Thr174Lys	missense	Exon 5 of 9	NP_001277262.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYT8	ENST00000341958.4	TSL:5 MANE Select	c.479C>A	p.Thr160Lys	missense	Exon 4 of 8	ENSP00000343691.3	Q8NBV8-4
SYT8	ENST00000381978.7	TSL:1	c.515C>A	p.Thr172Lys	missense	Exon 5 of 9	ENSP00000371406.3	H0Y3G9
SYT8	ENST00000490707.5	TSL:1	n.2456C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1428604

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708840

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32286

American (AMR)

AF:

0.00

AC:

AN:

39710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23886

East Asian (EAS)

AF:

0.00

AC:

AN:

39114

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097662

Other (OTH)

AF:

0.00

AC:

AN:

58902

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Benign

0.17

Eigen_PC

Benign

-0.089

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.73

M_CAP

Benign

0.046

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.98

MutationAssessor

Pathogenic

3.8

PhyloP100

1.9

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.3

REVEL

Benign

0.12

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.71

MutPred

0.61

Gain of methylation at T174 (P = 0.0135)

MVP

0.34

MPC

0.45

ClinPred

0.99

GERP RS

2.8

Varity_R

0.60

gMVP

0.81

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over