11-219538-A-G

Variant names:

• chr11-219538-A-G
• rs4758633
• NM_012239.6:c.970-497T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000382743.9(SIRT3):​c.970-497T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 151,962 control chromosomes in the GnomAD database, including 31,602 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 0.63 (31602 hom., cov: 31)
• Consequence: SIRT3 ENST00000382743.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.317
• Publications: 18 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000382743.9. 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.970-497T>C		intron	N/A	NP_036371.1
	SIRT3	NR_163391.1		n.804T>C		non_coding_transcript_exon	Exon 4 of 5
	SIRT3	NR_163402.1		n.1046T>C		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT3	ENST00000382743.9	TSL:1 MANE Select	c.970-497T>C		intron	N/A	ENSP00000372191.4
	SIRT3	ENST00000524564.5	TSL:2	c.778-497T>C		intron	N/A	ENSP00000432937.1
	SIRT3	ENST00000532956.5	TSL:2	c.808-497T>C		intron	N/A	ENSP00000433077.1

Frequencies

GnomAD3 genomes AF: 0.631 AC: 95754 AN: 151844 Hom.: 31543 Cov.: 31

Gnomad AFR AF: 0.831

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.541

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.575

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.631 AC: 95868 AN: 151962 Hom.: 31602 Cov.: 31 AF XY: 0.634 AC XY: 47068 AN XY: 74262

African (AFR) AF: 0.831 AC: 34456 AN: 41450

American (AMR) AF: 0.652 AC: 9945 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1448 AN: 3468

East Asian (EAS) AF: 0.717 AC: 3702 AN: 5162

South Asian (SAS) AF: 0.655 AC: 3151 AN: 4810

European-Finnish (FIN) AF: 0.541 AC: 5705 AN: 10536

Middle Eastern (MID) AF: 0.411 AC: 120 AN: 292

European-Non Finnish (NFE) AF: 0.527 AC: 35818 AN: 67970

Other (OTH) AF: 0.572 AC: 1203 AN: 2102

Alfa AF: 0.561 Hom.: 15782

Bravo AF: 0.649

Asia WGS AF: 0.687 AC: 2388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.2
DANN	Benign	0.58
PhyloP100		0.32
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: rs4758633; hg19: chr11-219538;