rs4746720

Positions:

• chr10-67917073-T-C
• chr10-67917073-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012238.5(SIRT1):​c.*480T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 152,736 control chromosomes in the GnomAD database, including 532 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 0.030 (532 hom., cov: 32)
  • Exomes 𝑓: 0.043 (0 hom.)
• Consequence: SIRT1 NM_012238.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRT1	NM_012238.5	c.*480T>C		3_prime_UTR_variant	9/9	ENST00000212015.11	NP_036370.2
SIRT1	NM_001142498.2	c.*480T>C		3_prime_UTR_variant	8/8		NP_001135970.1
SIRT1	NM_001314049.2	c.*480T>C		3_prime_UTR_variant	10/10		NP_001300978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIRT1	ENST00000212015.11	c.*480T>C		3_prime_UTR_variant	9/9	1	NM_012238.5	ENSP00000212015	P1
SIRT1	ENST00000403579.1	c.*480T>C		3_prime_UTR_variant	6/6	1		ENSP00000384063
SIRT1	ENST00000406900.5	c.*480T>C		3_prime_UTR_variant	7/7	2		ENSP00000384508
SIRT1	ENST00000432464.5	c.*480T>C		3_prime_UTR_variant	8/8	5		ENSP00000409208

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4594 AN: 152158 Hom.: 529 Cov.: 32

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.0973

Gnomad FIN AF: 0.0404

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.0435 AC: 20 AN: 460 Hom.: 0 Cov.: 0 AF XY: 0.0331 AC XY: 9 AN XY: 272

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0444

Gnomad4 NFE exome AF: 0.0500

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0302 AC: 4602 AN: 152276 Hom.: 532 Cov.: 32 AF XY: 0.0367 AC XY: 2733 AN XY: 74450

Gnomad4 AFR AF: 0.00476

Gnomad4 AMR AF: 0.0697

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.414

Gnomad4 SAS AF: 0.0974

Gnomad4 FIN AF: 0.0404

Gnomad4 NFE AF: 0.00295

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0128 Hom.: 352

Bravo AF: 0.0347

Asia WGS AF: 0.211 AC: 732 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.5
DANN	Benign	0.80

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

LitVar

Other links and lift over

dbSNP: rs4746720; hg19: chr10-69676830;