11-233212-C-A

Variant names:

• chr11-233212-C-A
• rs11555236
• NM_012239.6:c.477G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_012239.6(SIRT3):​c.477G>T​(p.Ser159Ser) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.16 (2339 hom., cov: 31)
  • Exomes 𝑓: 0.20 (29684 hom.)
• Consequence: SIRT3 NM_012239.6 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.384
• Publications: 34 publications found

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

Our verdict: Benign. The variant received -12 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 VariationId is 3060621.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
SIRT3	NM_012239.6	c.477G>T	p.Ser159Ser	synonymous_variant	Exon 3 of 7	ENST00000382743.9	NP_036371.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRT3	ENST00000382743.9	c.477G>T	p.Ser159Ser	synonymous_variant	Exon 3 of 7	1	NM_012239.6	ENSP00000372191.4

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

GnomAD2 exomes AF: 0.170 AC: 42446 AN: 250078 AF XY: 0.176

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 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

African (AFR) AF: 0.0344 AC: 1149 AN: 33380

American (AMR) AF: 0.112 AC: 5007 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 6749 AN: 26064

East Asian (EAS) AF: 0.134 AC: 5302 AN: 39678

South Asian (SAS) AF: 0.141 AC: 12126 AN: 86198

European-Finnish (FIN) AF: 0.214 AC: 11412 AN: 53386

Middle Eastern (MID) AF: 0.228 AC: 1316 AN: 5762

European-Non Finnish (NFE) AF: 0.210 AC: 233207 AN: 1110664

Other (OTH) AF: 0.191 AC: 11517 AN: 60298

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

African (AFR) AF: 0.0390 AC: 1616 AN: 41466

American (AMR) AF: 0.153 AC: 2342 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 873 AN: 3468

East Asian (EAS) AF: 0.112 AC: 581 AN: 5168

South Asian (SAS) AF: 0.147 AC: 707 AN: 4802

European-Finnish (FIN) AF: 0.224 AC: 2348 AN: 10494

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14476 AN: 67968

Other (OTH) AF: 0.180 AC: 379 AN: 2108

Alfa AF: 0.178 Hom.: 1870

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: no assertion criteria provided

Submissions by phenotype

SIRT3-related disorder Benign:1

Oct 23, 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
BayesDel_noAF	Benign	-0.34
CADD	Benign	9.9
DANN	Benign	0.74
PhyloP100		0.38
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

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