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GeneBe

11-224204-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_012239.6(SIRT3):c.843G>A(p.Pro281=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000427 in 1,614,110 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00073 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00040 ( 3 hom. )

Consequence

SIRT3
NM_012239.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.28
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 11-224204-C-T is Benign according to our data. Variant chr11-224204-C-T is described in ClinVar as [Benign]. Clinvar id is 3034628.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-3.28 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000729 (111/152326) while in subpopulation EAS AF= 0.0189 (98/5190). AF 95% confidence interval is 0.0159. There are 3 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SIRT3NM_012239.6 linkuse as main transcriptc.843G>A p.Pro281= synonymous_variant 5/7 ENST00000382743.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SIRT3ENST00000382743.9 linkuse as main transcriptc.843G>A p.Pro281= synonymous_variant 5/71 NM_012239.6 A2Q9NTG7-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000756
AC:
115
AN:
152208
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0196
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00144
AC:
362
AN:
250840
Hom.:
0
AF XY:
0.00144
AC XY:
195
AN XY:
135702
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0175
Gnomad SAS exome
AF:
0.000392
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000883
Gnomad OTH exome
AF:
0.00229
GnomAD4 exome
AF:
0.000395
AC:
578
AN:
1461784
Hom.:
3
Cov.:
33
AF XY:
0.000400
AC XY:
291
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0103
Gnomad4 SAS exome
AF:
0.000510
Gnomad4 FIN exome
AF:
0.0000937
Gnomad4 NFE exome
AF:
0.0000324
Gnomad4 OTH exome
AF:
0.00129
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000729
AC:
111
AN:
152326
Hom.:
3
Cov.:
32
AF XY:
0.000765
AC XY:
57
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0189
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000654
Hom.:
0
Bravo
AF:
0.000627
Asia WGS
AF:
0.0120
AC:
40
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

SIRT3-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 28, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
Cadd
Benign
0.14
Dann
Benign
0.60

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs12223279; hg19: chr11-224204; API