NM_012238.5:c.994T>C

Variant names:

• chr10-67906841-T-C
• rs2273773
• NM_012238.5:c.994T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012238.5(SIRT1):​c.994T>C​(p.Leu332Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0804 in 1,612,912 control chromosomes in the GnomAD database, including 7,456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (714 hom., cov: 32)
  • Exomes 𝑓: 0.081 (6742 hom.)
• Consequence: SIRT1 NM_012238.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.24
• Publications: 102 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-67906841-T-C is Benign according to our data. Variant chr10-67906841-T-C is described in ClinVar as Benign. ClinVar VariationId is 1561038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012238.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT1	NM_012238.5	MANE Select	c.994T>C	p.Leu332Leu	synonymous	Exon 5 of 9	NP_036370.2
	SIRT1	NM_001142498.2		c.109T>C	p.Leu37Leu	synonymous	Exon 4 of 8	NP_001135970.1
	SIRT1	NM_001314049.2		c.85T>C	p.Leu29Leu	synonymous	Exon 6 of 10	NP_001300978.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT1	ENST00000212015.11	TSL:1 MANE Select	c.994T>C	p.Leu332Leu	synonymous	Exon 5 of 9	ENSP00000212015.6
	SIRT1	ENST00000403579.1	TSL:1	c.85T>C	p.Leu29Leu	synonymous	Exon 2 of 6	ENSP00000384063.1
	SIRT1	ENST00000432464.5	TSL:5	c.109T>C	p.Leu37Leu	synonymous	Exon 4 of 8	ENSP00000409208.1

Frequencies

GnomAD3 genomes AF: 0.0756 AC: 11490 AN: 152082 Hom.: 713 Cov.: 32

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0652

Gnomad OTH AF: 0.0738

GnomAD2 exomes AF: 0.109 AC: 27242 AN: 249932 AF XY: 0.106

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.183

Gnomad ASJ exome AF: 0.0462

Gnomad EAS exome AF: 0.289

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.0991

GnomAD4 exome AF: 0.0809 AC: 118237 AN: 1460712 Hom.: 6742 Cov.: 31 AF XY: 0.0816 AC XY: 59262 AN XY: 726660

African (AFR) AF: 0.0236 AC: 789 AN: 33428

American (AMR) AF: 0.176 AC: 7821 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.0457 AC: 1194 AN: 26114

East Asian (EAS) AF: 0.310 AC: 12285 AN: 39584

South Asian (SAS) AF: 0.122 AC: 10505 AN: 86090

European-Finnish (FIN) AF: 0.140 AC: 7464 AN: 53386

Middle Eastern (MID) AF: 0.0949 AC: 547 AN: 5766

European-Non Finnish (NFE) AF: 0.0653 AC: 72580 AN: 1111522

Other (OTH) AF: 0.0837 AC: 5052 AN: 60354

GnomAD4 genome AF: 0.0755 AC: 11488 AN: 152200 Hom.: 714 Cov.: 32 AF XY: 0.0811 AC XY: 6035 AN XY: 74386

African (AFR) AF: 0.0265 AC: 1101 AN: 41562

American (AMR) AF: 0.119 AC: 1817 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 154 AN: 3472

East Asian (EAS) AF: 0.303 AC: 1570 AN: 5186

South Asian (SAS) AF: 0.124 AC: 597 AN: 4822

European-Finnish (FIN) AF: 0.148 AC: 1562 AN: 10568

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0652 AC: 4432 AN: 67996

Other (OTH) AF: 0.0725 AC: 153 AN: 2110

Alfa AF: 0.0672 Hom.: 864

Bravo AF: 0.0727

Asia WGS AF: 0.182 AC: 631 AN: 3476

EpiCase AF: 0.0667

EpiControl AF: 0.0639

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2273773; hg19: chr10-69666598; COSMIC: COSV53018003;