Genetic Variant SIRT3:p.Val208Ile (chr11-233067-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_012239.6(SIRT3):c.622G>A(p.Val208Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,613,830 control chromosomes in the GnomAD database, including 32,075 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.16 ( 2346 hom., cov: 31)

Exomes 𝑓: 0.20 ( 29729 hom. )

Consequence

SIRT3
NM_012239.6 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.829

Publications

57 publications found

Variant links:

Genes affected

SIRT3 (HGNC:14931): (sirtuin 3) SIRT3 encodes a member of the sirtuin family of class III histone deacetylases, homologs to the yeast Sir2 protein. The encoded protein is found exclusively in mitochondria, where it can eliminate reactive oxygen species, inhibit apoptosis, and prevent the formation of cancer cells. SIRT3 has far-reaching effects on nuclear gene expression, cancer, cardiovascular disease, neuroprotection, aging, and metabolic control. [provided by RefSeq, May 2019]

SIRT3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025118291).

BP6

Variant 11-233067-C-T is Benign according to our data. Variant chr11-233067-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060261.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT3	NM_012239.6 link	c.622G>A	p.Val208Ile	missense_variant	Exon 3 of 7	ENST00000382743.9	NP_036371.1	Q9NTG7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRT3	ENST00000382743.9 link	c.622G>A	p.Val208Ile	missense_variant	Exon 3 of 7	1	NM_012239.6	ENSP00000372191.4		Q9NTG7-1

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23750

AN:

151932

Hom.:

2348

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0388

Gnomad AMI

AF:

0.382

Gnomad AMR

AF:

0.154

Gnomad ASJ

AF:

0.252

Gnomad EAS

AF:

0.112

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.224

Gnomad MID

AF:

0.232

Gnomad NFE

AF:

0.213

Gnomad OTH

AF:

0.182

GnomAD2 exomes

AF:

0.170

AC:

42782

AN:

251474

AF XY:

0.176

show subpopulations

Gnomad AFR exome

AF:

0.0330

Gnomad AMR exome

AF:

0.106

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.0960

Gnomad FIN exome

AF:

0.220

Gnomad NFE exome

AF:

0.210

Gnomad OTH exome

AF:

0.191

GnomAD4 exome

AF:

0.197

AC:

288203

AN:

1461780

Hom.:

29729

Cov.:

AF XY:

0.197

AC XY:

143334

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.0344

AC:

1151

AN:

33480

American (AMR)

AF:

0.112

AC:

5004

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.259

AC:

6768

AN:

26136

East Asian (EAS)

AF:

0.134

AC:

5305

AN:

39700

South Asian (SAS)

AF:

0.141

AC:

12149

AN:

86258

European-Finnish (FIN)

AF:

0.214

AC:

11421

AN:

53416

Middle Eastern (MID)

AF:

0.230

AC:

1324

AN:

5768

European-Non Finnish (NFE)

AF:

0.210

AC:

233543

AN:

1111906

Other (OTH)

AF:

0.191

AC:

11538

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

13305

26610

39914

53219

66524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7846

15692

23538

31384

39230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.156

AC:

23737

AN:

152050

Hom.:

2346

Cov.:

AF XY:

0.156

AC XY:

11602

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.0388

AC:

1612

AN:

41512

American (AMR)

AF:

0.153

AC:

2343

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.252

AC:

874

AN:

3468

East Asian (EAS)

AF:

0.112

AC:

583

AN:

5184

South Asian (SAS)

AF:

0.147

AC:

706

AN:

4816

European-Finnish (FIN)

AF:

0.224

AC:

2357

AN:

10538

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.213

AC:

14473

AN:

67946

Other (OTH)

AF:

0.180

AC:

378

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

932

1865

2797

3730

4662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

264

528

792

1056

1320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.197

Hom.:

11606

Bravo

AF:

0.146

ESP6500AA

AF:

0.0433

AC:

191

ESP6500EA

AF:

0.213

AC:

1831

ExAC

AF:

0.166

AC:

20202

Asia WGS

AF:

0.124

AC:

431

AN:

3478

EpiCase

AF:

0.232

EpiControl

AF:

0.231

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

SIRT3-related disorder

Benign:1

Nov 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.090

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.047

T;.;T;.;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.30

T;T;T;T;T;T

MetaRNN

Benign

0.0025

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.85

N;.;.;.;.;.

PhyloP100

-0.83

PrimateAI

Benign

0.23

PROVEAN

Benign

0.040

N;N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

0.78

T;T;T;T;T;.

Polyphen

0.0020

B;B;B;B;.;.

Vest4

0.055

MPC

0.15

ClinPred

0.0019

GERP RS

-3.3

Varity_R

0.051

gMVP

0.59

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over