6-13591858-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012241.5(SIRT5):c.439C>A(p.Arg147Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SIRT5 NM_012241.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT5	NM_012241.5	c.439C>A	p.Arg147Ser	missense_variant	5/10	ENST00000606117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT5	ENST00000606117.2	c.439C>A	p.Arg147Ser	missense_variant	5/10	1	NM_012241.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461704 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727146

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.439C>A (p.R147S) alteration is located in exon 5 (coding exon 3) of the SIRT5 gene. This alteration results from a C to A substitution at nucleotide position 439, causing the arginine (R) at amino acid position 147 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	0.0066
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.22	T;T;T;.
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.44, 0.22	.;.;B;B
Vest4		0.67
MutPred		0.61		.;Gain of ubiquitination at K152 (P = 0.0338);Gain of ubiquitination at K152 (P = 0.0338);Gain of ubiquitination at K152 (P = 0.0338);
MVP		0.58
MPC		0.13
ClinPred		0.85	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-13592090;