NM_012239.6:c.785C>A

Variant names:

• chr11-230474-G-T
• rs61748606
• NM_012239.6:c.785C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012239.6(SIRT3):​c.785C>A​(p.Pro262His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,505,370 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (40 hom.)
• Consequence: SIRT3 NM_012239.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.70
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055104196).
• BP6: Variant 11-230474-G-T is Benign according to our data. Variant chr11-230474-G-T is described in ClinVar as Benign. ClinVar VariationId is 782538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00984 (1499/152262) while in subpopulation AFR AF = 0.023 (956/41546). AF 95% confidence interval is 0.0218. There are 13 homozygotes in GnomAd4. There are 698 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT3	NM_012239.6	MANE Select	c.785C>A	p.Pro262His	missense	Exon 4 of 7	NP_036371.1	Q9NTG7-1
	SIRT3	NM_001370310.1		c.785C>A	p.Pro262His	missense	Exon 4 of 7	NP_001357239.1
	SIRT3	NM_001370312.1		c.593C>A	p.Pro198His	missense	Exon 3 of 6	NP_001357241.1	E9PN58

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT3	ENST00000382743.9	TSL:1 MANE Select	c.785C>A	p.Pro262His	missense	Exon 4 of 7	ENSP00000372191.4	Q9NTG7-1
	SIRT3	ENST00000941617.1		c.785C>A	p.Pro262His	missense	Exon 4 of 7	ENSP00000611676.1
	SIRT3	ENST00000852931.1		c.785C>A	p.Pro262His	missense	Exon 4 of 7	ENSP00000522990.1

Frequencies

GnomAD3 genomes AF: 0.00982 AC: 1494 AN: 152144 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00545

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00519 AC: 976 AN: 187926 AF XY: 0.00469

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.00738

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000979

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.00754

GnomAD4 exome AF: 0.00550 AC: 7445 AN: 1353108 Hom.: 40 Cov.: 30 AF XY: 0.00545 AC XY: 3651 AN XY: 669682

African (AFR) AF: 0.0205 AC: 586 AN: 28534

American (AMR) AF: 0.00813 AC: 243 AN: 29884

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 28 AN: 23002

East Asian (EAS) AF: 0.00 AC: 0 AN: 33000

South Asian (SAS) AF: 0.00193 AC: 137 AN: 71026

European-Finnish (FIN) AF: 0.000487 AC: 25 AN: 51360

Middle Eastern (MID) AF: 0.0167 AC: 90 AN: 5404

European-Non Finnish (NFE) AF: 0.00563 AC: 5946 AN: 1055694

Other (OTH) AF: 0.00706 AC: 390 AN: 55204

GnomAD4 genome AF: 0.00984 AC: 1499 AN: 152262 Hom.: 13 Cov.: 32 AF XY: 0.00938 AC XY: 698 AN XY: 74432

African (AFR) AF: 0.0230 AC: 956 AN: 41546

American (AMR) AF: 0.00824 AC: 126 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00547 AC: 372 AN: 68018

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00717 Hom.: 18

Bravo AF: 0.0115

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00576 AC: 699

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.7
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.16
Sift	Uncertain	0.022	D
Sift4G	Benign	0.064	T
Polyphen		0.98	D
Vest4		0.21
MVP		0.50
MPC		0.30
ClinPred		0.030	T
GERP RS		2.1
Varity_R		0.18
gMVP		0.47
Mutation Taster		=93/7	polymorphism

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: rs61748606; hg19: chr11-230474;