chr11-224063-G-A

Variant names:

• chr11-224063-G-A
• rs12222188
• NM_012239.6:c.969+15C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012239.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT3	NM_012239.6	MANE Select	c.969+15C>T		intron	N/A	NP_036371.1
	SIRT3	NM_001370310.1		c.969+15C>T		intron	N/A	NP_001357239.1
	SIRT3	NM_001370312.1		c.777+15C>T		intron	N/A	NP_001357241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT3	ENST00000382743.9	TSL:1 MANE Select	c.969+15C>T		intron	N/A	ENSP00000372191.4
	SIRT3	ENST00000524564.5	TSL:2	c.777+15C>T		intron	N/A	ENSP00000432937.1
	SIRT3	ENST00000532956.5	TSL:2	c.808-5022C>T		intron	N/A	ENSP00000433077.1

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

GnomAD2 exomes AF: 0.0564 AC: 14133 AN: 250800 AF XY: 0.0575

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 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

African (AFR) AF: 0.0634 AC: 2110 AN: 33302

American (AMR) AF: 0.0654 AC: 2908 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 415 AN: 25896

East Asian (EAS) AF: 0.126 AC: 4974 AN: 39538

South Asian (SAS) AF: 0.0926 AC: 7759 AN: 83768

European-Finnish (FIN) AF: 0.0187 AC: 990 AN: 53018

Middle Eastern (MID) AF: 0.0481 AC: 274 AN: 5692

European-Non Finnish (NFE) AF: 0.0405 AC: 44818 AN: 1107006

Other (OTH) AF: 0.0488 AC: 2926 AN: 59918

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

African (AFR) AF: 0.0587 AC: 2418 AN: 41192

American (AMR) AF: 0.0650 AC: 980 AN: 15070

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 51 AN: 3426

East Asian (EAS) AF: 0.141 AC: 720 AN: 5112

South Asian (SAS) AF: 0.0945 AC: 442 AN: 4678

European-Finnish (FIN) AF: 0.0189 AC: 198 AN: 10466

Middle Eastern (MID) AF: 0.0282 AC: 8 AN: 284

European-Non Finnish (NFE) AF: 0.0338 AC: 2269 AN: 67190

Other (OTH) AF: 0.0415 AC: 86 AN: 2074

Alfa AF: 0.0360 Hom.: 55

Bravo AF: 0.0555

Asia WGS AF: 0.118 AC: 407 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.44
PhyloP100		0.50
Mutation Taster		=100/0	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: rs12222188; hg19: chr11-224063;