rs3740053

Variant names:

• chr10-67884577-A-G
• rs3740053
• NM_012238.5:c.-145A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_012238.5(SIRT1):​c.-145A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0761 in 945,574 control chromosomes in the GnomAD database, including 4,095 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 0.076 (727 hom., cov: 35)
  • Exomes 𝑓: 0.076 (3368 hom.)
• Consequence: SIRT1 NM_012238.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.547
• Publications: 14 publications found

Genes affected

SIRT1 (HGNC:14929): (sirtuin 1) 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 I of the sirtuin family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2008]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT1	NM_012238.5	c.-145A>G		upstream_gene_variant		ENST00000212015.11	NP_036370.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRT1	ENST00000212015.11	c.-145A>G		upstream_gene_variant		1	NM_012238.5	ENSP00000212015.6

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 11558 AN: 152032 Hom.: 726 Cov.: 35

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.0727

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0659

Gnomad OTH AF: 0.0745

GnomAD4 exome AF: 0.0762 AC: 60447 AN: 793424 Hom.: 3368 AF XY: 0.0758 AC XY: 28859 AN XY: 380606

African (AFR) AF: 0.0238 AC: 408 AN: 17114

American (AMR) AF: 0.148 AC: 1107 AN: 7474

Ashkenazi Jewish (ASJ) AF: 0.0460 AC: 548 AN: 11922

East Asian (EAS) AF: 0.320 AC: 7777 AN: 24296

South Asian (SAS) AF: 0.134 AC: 1780 AN: 13248

European-Finnish (FIN) AF: 0.137 AC: 2793 AN: 20456

Middle Eastern (MID) AF: 0.0975 AC: 227 AN: 2328

European-Non Finnish (NFE) AF: 0.0650 AC: 43071 AN: 663044

Other (OTH) AF: 0.0816 AC: 2736 AN: 33542

GnomAD4 genome AF: 0.0760 AC: 11556 AN: 152150 Hom.: 727 Cov.: 35 AF XY: 0.0819 AC XY: 6094 AN XY: 74394

African (AFR) AF: 0.0268 AC: 1114 AN: 41516

American (AMR) AF: 0.119 AC: 1819 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 141 AN: 3470

East Asian (EAS) AF: 0.302 AC: 1559 AN: 5166

South Asian (SAS) AF: 0.130 AC: 628 AN: 4834

European-Finnish (FIN) AF: 0.147 AC: 1560 AN: 10598

Middle Eastern (MID) AF: 0.120 AC: 35 AN: 292

European-Non Finnish (NFE) AF: 0.0659 AC: 4479 AN: 67964

Other (OTH) AF: 0.0733 AC: 155 AN: 2116

Alfa AF: 0.0686 Hom.: 61

Bravo AF: 0.0733

Asia WGS AF: 0.183 AC: 633 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.75
PhyloP100		0.55
PromoterAI		-0.0078	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3740053; hg19: chr10-69644335;