rs11246020

Positions:

• chr11-233067-C-A
• chr11-233067-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012239.6(SIRT3):​c.622G>T​(p.Val208Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V208I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SIRT3 NM_012239.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.829

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04883623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT3	NM_012239.6	c.622G>T	p.Val208Phe	missense_variant	3/7	ENST00000382743.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT3	ENST00000382743.9	c.622G>T	p.Val208Phe	missense_variant	3/7	1	NM_012239.6	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.22
DANN	Benign	0.84
DEOGEN2	Benign	0.092	T;.;T;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.56	T;T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.049	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.31	N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.37	T;T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T;.
Polyphen		0.031	B;B;B;B;.;.
Vest4		0.16
MutPred		0.35		Gain of ubiquitination at K205 (P = 0.1222);.;.;Gain of ubiquitination at K205 (P = 0.1222);.;.;
MVP		0.076
MPC		0.26
ClinPred		0.095	T
GERP RS		-3.3
Varity_R		0.13
gMVP		0.79

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: rs11246020; hg19: chr11-233067;