11-230474-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 12/20 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, single submitter B:1
• Conservation: PhyloP100: 1.70

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 -14 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 id is 782538.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT3	NM_012239.6	c.785C>A	p.Pro262His	missense_variant	4/7	ENST00000382743.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT3	ENST00000382743.9	c.785C>A	p.Pro262His	missense_variant	4/7	1	NM_012239.6	A2

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

GnomAD3 exomes AF: 0.00519 AC: 976 AN: 187926 Hom.: 4 AF XY: 0.00469 AC XY: 483 AN XY: 103086

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 SAS exome AF: 0.00174

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

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.00813

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00193

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.00563

Gnomad4 OTH exome AF: 0.00706

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

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.00824

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00547

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00621 Hom.: 9

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.84	T;T;T;D;T
MetaRNN	Benign	0.0055	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N;N;N;D;N
REVEL	Benign	0.16
Sift	Uncertain	0.022	D;T;D;D;T
Sift4G	Benign	0.064	T;T;T;D;T
Polyphen		0.98	D;P;D;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

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: rs61748606; hg19: chr11-230474;