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GeneBe

11-218907-G-A

Variant summary

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

The NM_012239.6(SIRT3):c.1104C>T(p.His368=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,614,118 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0088 ( 18 hom., cov: 32)
Exomes 𝑓: 0.00088 ( 24 hom. )

Consequence

SIRT3
NM_012239.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.52
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=-0.81).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 11-218907-G-A is Benign according to our data. Variant chr11-218907-G-A is described in ClinVar as [Benign]. Clinvar id is 3056505.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=-2.52 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00876 (1333/152234) while in subpopulation AFR AF= 0.0304 (1261/41530). AF 95% confidence interval is 0.029. There are 18 homozygotes in gnomad4. There are 649 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 18 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SIRT3NM_012239.6 linkuse as main transcriptc.1104C>T p.His368= synonymous_variant 6/7 ENST00000382743.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SIRT3ENST00000382743.9 linkuse as main transcriptc.1104C>T p.His368= synonymous_variant 6/71 NM_012239.6 A2Q9NTG7-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00874
AC:
1329
AN:
152116
Hom.:
18
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0304
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00275
Gnomad ASJ
AF:
0.00202
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00336
GnomAD3 exomes
AF:
0.00237
AC:
597
AN:
251466
Hom.:
7
AF XY:
0.00187
AC XY:
254
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.0307
Gnomad AMR exome
AF:
0.00147
Gnomad ASJ exome
AF:
0.00119
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000392
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000114
Gnomad OTH exome
AF:
0.00163
GnomAD4 exome
AF:
0.000882
AC:
1290
AN:
1461884
Hom.:
24
Cov.:
32
AF XY:
0.000749
AC XY:
545
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.0296
Gnomad4 AMR exome
AF:
0.00150
Gnomad4 ASJ exome
AF:
0.00115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000290
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.0000477
Gnomad4 OTH exome
AF:
0.00179
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00876
AC:
1333
AN:
152234
Hom.:
18
Cov.:
32
AF XY:
0.00872
AC XY:
649
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.0304
Gnomad4 AMR
AF:
0.00275
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00333
Alfa
AF:
0.00469
Hom.:
4
Bravo
AF:
0.00997
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

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 SciencesMar 26, 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
-0.81
Cadd
Benign
1.2
Dann
Benign
0.80
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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: rs74477499; hg19: chr11-218907; COSMIC: COSV57344239; COSMIC: COSV57344239; API