6-13599071-C-T

Variant names:

• chr6-13599071-C-T
• rs3757261
• NM_012241.5:c.657C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 23 publications found

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]

LOC105374938 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SIRT5	NM_012241.5	c.657C>T	p.His219His	synonymous_variant	Exon 8 of 10	ENST00000606117.2	NP_036373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRT5	ENST00000606117.2	c.657C>T	p.His219His	synonymous_variant	Exon 8 of 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

GnomAD2 exomes AF: 0.203 AC: 50937 AN: 251236 AF XY: 0.211

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 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

African (AFR) AF: 0.0646 AC: 2161 AN: 33472

American (AMR) AF: 0.172 AC: 7684 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 5798 AN: 26132

East Asian (EAS) AF: 0.167 AC: 6644 AN: 39694

South Asian (SAS) AF: 0.226 AC: 19455 AN: 86200

European-Finnish (FIN) AF: 0.192 AC: 10243 AN: 53408

Middle Eastern (MID) AF: 0.306 AC: 1761 AN: 5764

European-Non Finnish (NFE) AF: 0.230 AC: 255508 AN: 1111828

Other (OTH) AF: 0.223 AC: 13476 AN: 60358

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

African (AFR) AF: 0.0684 AC: 2841 AN: 41518

American (AMR) AF: 0.192 AC: 2934 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 791 AN: 3472

East Asian (EAS) AF: 0.180 AC: 925 AN: 5144

South Asian (SAS) AF: 0.226 AC: 1086 AN: 4808

European-Finnish (FIN) AF: 0.186 AC: 1958 AN: 10536

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.230 AC: 15621 AN: 67948

Other (OTH) AF: 0.212 AC: 446 AN: 2108

Alfa AF: 0.218 Hom.: 12908

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
PhyloP100		-0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3757261; hg19: chr6-13599303; COSMIC: COSV63080610;