rs28365927

chr11-236091-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012239.6(SIRT3):c.238C>T(p.Arg80Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,561,618 control chromosomes in the GnomAD database, including 19,156 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1471 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17685 hom.)
• Consequence: SIRT3 NM_012239.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0360

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008159429).
• BP6: Variant 11-236091-G-A is Benign according to our data. Variant chr11-236091-G-A is described in ClinVar as [Benign]. Clinvar id is 3057000.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT3	NM_012239.6	c.238C>T	p.Arg80Trp	missense_variant	1/7	ENST00000382743.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT3	ENST00000382743.9	c.238C>T	p.Arg80Trp	missense_variant	1/7	1	NM_012239.6	A2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19568 AN: 152102 Hom.: 1471 Cov.: 32

Gnomad AFR AF: 0.0853

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.0976

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.160 AC: 30303 AN: 188822 Hom.: 2965 AF XY: 0.171 AC XY: 17770 AN XY: 103912

Gnomad AFR exome AF: 0.0840

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.125

Gnomad SAS exome AF: 0.350

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.150 AC: 210798 AN: 1409396 Hom.: 17685 Cov.: 32 AF XY: 0.155 AC XY: 108375 AN XY: 697412

Gnomad4 AFR exome AF: 0.0862

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.129 AC: 19565 AN: 152222 Hom.: 1471 Cov.: 32 AF XY: 0.131 AC XY: 9774 AN XY: 74430

Gnomad4 AFR AF: 0.0851

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.0976

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.121

Alfa AF: 0.140 Hom.: 2289

Bravo AF: 0.121

TwinsUK AF: 0.138 AC: 511

ALSPAC AF: 0.148 AC: 569

ESP6500AA AF: 0.0837 AC: 367

ESP6500EA AF: 0.142 AC: 1217

ExAC AF: 0.144 AC: 17301

Asia WGS AF: 0.207 AC: 720 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SIRT3-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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	0.15
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Benign	0.75
DEOGEN2	Benign	0.26	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.75	T;T;T
MetaRNN	Benign	0.0082	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.85	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D;T
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.0040	B;B;B
Vest4		0.059
MPC		0.55
ClinPred		0.075	T
GERP RS		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.28
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs28365927; hg19: chr11-236091;