rs12222188

Positions:

• chr11-224063-G-A
• chr11-224063-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012239.6(SIRT3):​c.969+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 1,602,992 control chromosomes in the GnomAD database, including 2,692 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.048 (338 hom., cov: 31)
  • Exomes 𝑓: 0.046 (2354 hom.)
• Consequence: SIRT3 NM_012239.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.503

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRT3	NM_012239.6	c.969+15C>T		intron_variant		ENST00000382743.9	NP_036371.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIRT3	ENST00000382743.9	c.969+15C>T		intron_variant		1	NM_012239.6	ENSP00000372191.4

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7163 AN: 150284 Hom.: 338 Cov.: 31

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0643

Gnomad ASJ AF: 0.0149

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.0948

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.0296

Gnomad NFE AF: 0.0338

Gnomad OTH AF: 0.0409

GnomAD3 exomes AF: 0.0564 AC: 14133 AN: 250800 Hom.: 595 AF XY: 0.0575 AC XY: 7796 AN XY: 135624

Gnomad AFR exome AF: 0.0627

Gnomad AMR exome AF: 0.0676

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.132

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.0380

Gnomad OTH exome AF: 0.0510

GnomAD4 exome AF: 0.0462 AC: 67174 AN: 1452590 Hom.: 2354 Cov.: 33 AF XY: 0.0472 AC XY: 34047 AN XY: 721970

Gnomad4 AFR exome AF: 0.0634

Gnomad4 AMR exome AF: 0.0654

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.0926

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0405

Gnomad4 OTH exome AF: 0.0488

GnomAD4 genome AF: 0.0477 AC: 7172 AN: 150402 Hom.: 338 Cov.: 31 AF XY: 0.0479 AC XY: 3522 AN XY: 73490

Gnomad4 AFR AF: 0.0587

Gnomad4 AMR AF: 0.0650

Gnomad4 ASJ AF: 0.0149

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.0945

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.0338

Gnomad4 OTH AF: 0.0415

Alfa AF: 0.0318 Hom.: 39

Bravo AF: 0.0555

Asia WGS AF: 0.118 AC: 407 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.44

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: rs12222188; hg19: chr11-224063;