rs3757261

Positions:

• chr6-13599071-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_012241.5(SIRT5):​c.657C>T​(p.His219His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,613,570 control chromosomes in the GnomAD database, including 39,645 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2828 hom., cov: 31)
  • Exomes 𝑓: 0.22 (36817 hom.)
• Consequence: SIRT5 NM_012241.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.140

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]

SIRT5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=-0.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRT5	NM_012241.5	c.657C>T	p.His219His	synonymous_variant	8/10	ENST00000606117.2	NP_036373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIRT5	ENST00000606117.2	c.657C>T	p.His219His	synonymous_variant	8/10	1	NM_012241.5	ENSP00000476228.1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27018 AN: 151892 Hom.: 2826 Cov.: 31

Gnomad AFR AF: 0.0686

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.212

GnomAD3 exomes AF: 0.203 AC: 50937 AN: 251236 Hom.: 5527 AF XY: 0.211 AC XY: 28666 AN XY: 135774

Gnomad AFR exome AF: 0.0640

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.172

Gnomad SAS exome AF: 0.227

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.231

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.221 AC: 322730 AN: 1461560 Hom.: 36817 Cov.: 33 AF XY: 0.222 AC XY: 161671 AN XY: 727064

Gnomad4 AFR exome AF: 0.0646

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.167

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.223

GnomAD4 genome AF: 0.178 AC: 27017 AN: 152010 Hom.: 2828 Cov.: 31 AF XY: 0.175 AC XY: 12990 AN XY: 74282

Gnomad4 AFR AF: 0.0684

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.212

Alfa AF: 0.226 Hom.: 9943

Bravo AF: 0.173

Asia WGS AF: 0.196 AC: 680 AN: 3478

EpiCase AF: 0.244

EpiControl AF: 0.239

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.39
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs3757261; hg19: chr6-13599303; COSMIC: COSV63080610;