6-13600840-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_012241.5(SIRT5):c.748A>G(p.Thr250Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,611,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
SIRT5
NM_012241.5 missense
NM_012241.5 missense
Scores
9
5
3
Clinical Significance
Conservation
PhyloP100: 8.68
Genes affected
SIRT5 (HGNC:14933): (sirtuin 5) This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class III of the sirtuin family. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.92
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SIRT5 | NM_012241.5 | c.748A>G | p.Thr250Ala | missense_variant | 9/10 | ENST00000606117.2 | |
LOC105374938 | XR_007059460.1 | n.2165-1199T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIRT5 | ENST00000606117.2 | c.748A>G | p.Thr250Ala | missense_variant | 9/10 | 1 | NM_012241.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000406 AC: 1AN: 246286Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133268
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1459276Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4AN XY: 725862
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 2023 | The c.748A>G (p.T250A) alteration is located in exon 9 (coding exon 7) of the SIRT5 gene. This alteration results from a A to G substitution at nucleotide position 748, causing the threonine (T) at amino acid position 250 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;.
REVEL
Pathogenic
Sift
Benign
D;D;D;.
Sift4G
Uncertain
D;D;D;D
Polyphen
1.0, 1.0
.;.;D;D
Vest4
MVP
MPC
0.43
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at