NM_012239.6:c.238C>T

Variant names:

• chr11-236091-G-A
• rs28365927
• NM_012239.6:c.238C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_012239.6(SIRT3):​c.238C>T​(p.Arg80Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,561,618 control chromosomes in the GnomAD database, including 19,156 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1471 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17685 hom.)
• Consequence: SIRT3 NM_012239.6 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0360
• Publications: 31 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008159429).
• BP6: Variant 11-236091-G-A is Benign according to our data. Variant chr11-236091-G-A is described in ClinVar as Benign. ClinVar VariationId is 3057000.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.325 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.238C>T	p.Arg80Trp	missense	Exon 1 of 7	NP_036371.1
	SIRT3	NM_001370310.1		c.238C>T	p.Arg80Trp	missense	Exon 1 of 7	NP_001357239.1
	SIRT3	NM_001370312.1		c.238C>T	p.Arg80Trp	missense	Exon 1 of 6	NP_001357241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT3	ENST00000382743.9	TSL:1 MANE Select	c.238C>T	p.Arg80Trp	missense	Exon 1 of 7	ENSP00000372191.4
	SIRT3	ENST00000525237.1	TSL:3	c.-141C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000436085.1
	SIRT3	ENST00000524564.5	TSL:2	c.238C>T	p.Arg80Trp	missense	Exon 1 of 6	ENSP00000432937.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19568 AN: 152102 Hom.: 1471 Cov.: 32

Gnomad AFR AF: 0.0853

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.0976

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.160 AC: 30303 AN: 188822 AF XY: 0.171

Gnomad AFR exome AF: 0.0840

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.150 AC: 210798 AN: 1409396 Hom.: 17685 Cov.: 32 AF XY: 0.155 AC XY: 108375 AN XY: 697412

African (AFR) AF: 0.0862 AC: 2689 AN: 31196

American (AMR) AF: 0.120 AC: 4404 AN: 36640

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 3932 AN: 24550

East Asian (EAS) AF: 0.143 AC: 5183 AN: 36334

South Asian (SAS) AF: 0.341 AC: 27568 AN: 80774

European-Finnish (FIN) AF: 0.104 AC: 5287 AN: 50682

Middle Eastern (MID) AF: 0.201 AC: 1123 AN: 5600

European-Non Finnish (NFE) AF: 0.140 AC: 152040 AN: 1085838

Other (OTH) AF: 0.148 AC: 8572 AN: 57782

GnomAD4 genome AF: 0.129 AC: 19565 AN: 152222 Hom.: 1471 Cov.: 32 AF XY: 0.131 AC XY: 9774 AN XY: 74430

African (AFR) AF: 0.0851 AC: 3535 AN: 41540

American (AMR) AF: 0.134 AC: 2052 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 550 AN: 3468

East Asian (EAS) AF: 0.133 AC: 689 AN: 5182

South Asian (SAS) AF: 0.338 AC: 1634 AN: 4828

European-Finnish (FIN) AF: 0.0976 AC: 1036 AN: 10616

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9633 AN: 67972

Other (OTH) AF: 0.121 AC: 256 AN: 2114

Alfa AF: 0.134 Hom.: 4764

Bravo AF: 0.121

TwinsUK AF: 0.138 AC: 511

ALSPAC AF: 0.148 AC: 569

ESP6500AA AF: 0.0837 AC: 367

ESP6500EA AF: 0.142 AC: 1217

ExAC AF: 0.144 AC: 17301

Asia WGS AF: 0.207 AC: 720 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SIRT3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.75
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.036
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.018	D
Polyphen		0.0040	B
Vest4		0.059
MPC		0.55
ClinPred		0.075	T
GERP RS		-0.17
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.28
gMVP		0.52
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs28365927; hg19: chr11-236091; COSMIC: COSV107426050;