rs11555236

chr11-233212-C-Achr11-233212-C-Gchr11-233212-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_012239.6(SIRT3):c.477G>T(p.Ser159=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,611,950 control chromosomes in the GnomAD database, including 32,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2339 hom., cov: 31)
  • Exomes 𝑓: 0.20 (29684 hom.)
• Consequence: SIRT3 NM_012239.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.384

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 11-233212-C-A is Benign according to our data. Variant chr11-233212-C-A is described in ClinVar as [Benign]. Clinvar id is 3060621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.384 with no splicing effect.
• 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/exons	MANE	UniProt
SIRT3	NM_012239.6	c.477G>T	p.Ser159=	synonymous_variant	3/7	ENST00000382743.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT3	ENST00000382743.9	c.477G>T	p.Ser159=	synonymous_variant	3/7	1	NM_012239.6	A2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23745 AN: 151826 Hom.: 2341 Cov.: 31

Gnomad AFR AF: 0.0389

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.170 AC: 42446 AN: 250078 Hom.: 4101 AF XY: 0.176 AC XY: 23729 AN XY: 135144

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.0957

Gnomad SAS exome AF: 0.142

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.209

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.197 AC: 287785 AN: 1460006 Hom.: 29684 Cov.: 33 AF XY: 0.197 AC XY: 143090 AN XY: 726092

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.259

Gnomad4 EAS exome AF: 0.134

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.191

GnomAD4 genome AF: 0.156 AC: 23734 AN: 151944 Hom.: 2339 Cov.: 31 AF XY: 0.156 AC XY: 11608 AN XY: 74218

Gnomad4 AFR AF: 0.0390

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.213

Gnomad4 OTH AF: 0.180

Alfa AF: 0.178 Hom.: 1652

Bravo AF: 0.146

Asia WGS AF: 0.123 AC: 430 AN: 3478

EpiCase AF: 0.232

EpiControl AF: 0.230

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SIRT3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 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
BayesDel_noAF	Benign	-0.34
Cadd	Benign	9.9
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs11555236; hg19: chr11-233212; COSMIC: COSV61501069; COSMIC: COSV61501069;