NM_012238.5:c.110C>T

Variant names:

• chr10-67884831-C-T
• rs548590752
• NM_012238.5:c.110C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_012238.5(SIRT1):​c.110C>T​(p.Pro37Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,223,802 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P37A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (4 hom.)
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.369
• Publications: 6 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]

SIRT1 Gene-Disease associations (from GenCC):

• autoimmune disease

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• monogenic diabetes

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008982778).
• BP6: Variant 10-67884831-C-T is Benign according to our data. Variant chr10-67884831-C-T is described in ClinVar as Benign. ClinVar VariationId is 1541459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 443 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT1	NM_012238.5	MANE Select	c.110C>T	p.Pro37Leu	missense	Exon 1 of 9	NP_036370.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT1	ENST00000212015.11	TSL:1 MANE Select	c.110C>T	p.Pro37Leu	missense	Exon 1 of 9	ENSP00000212015.6	Q96EB6-1
	SIRT1	ENST00000923649.1		c.110C>T	p.Pro37Leu	missense	Exon 1 of 10	ENSP00000593708.1
	SIRT1	ENST00000959939.1		c.110C>T	p.Pro37Leu	missense	Exon 1 of 9	ENSP00000629998.1

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 444 AN: 151296 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00894

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00427

Gnomad OTH AF: 0.00289

GnomAD2 exomes AF: 0.00 AC: 0 AN: 156 AF XY: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

GnomAD4 exome AF: 0.00320 AC: 3436 AN: 1072400 Hom.: 4 Cov.: 34 AF XY: 0.00324 AC XY: 1641 AN XY: 506310

African (AFR) AF: 0.000398 AC: 9 AN: 22586

American (AMR) AF: 0.00123 AC: 10 AN: 8126

Ashkenazi Jewish (ASJ) AF: 0.00121 AC: 17 AN: 13998

East Asian (EAS) AF: 0.000153 AC: 4 AN: 26060

South Asian (SAS) AF: 0.00206 AC: 40 AN: 19444

European-Finnish (FIN) AF: 0.00789 AC: 166 AN: 21042

Middle Eastern (MID) AF: 0.00278 AC: 8 AN: 2874

European-Non Finnish (NFE) AF: 0.00337 AC: 3084 AN: 915180

Other (OTH) AF: 0.00227 AC: 98 AN: 43090

GnomAD4 genome AF: 0.00293 AC: 443 AN: 151402 Hom.: 0 Cov.: 33 AF XY: 0.00309 AC XY: 229 AN XY: 74024

African (AFR) AF: 0.000483 AC: 20 AN: 41392

American (AMR) AF: 0.00164 AC: 25 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000394 AC: 2 AN: 5082

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.00894 AC: 93 AN: 10404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00427 AC: 289 AN: 67718

Other (OTH) AF: 0.00286 AC: 6 AN: 2096

Alfa AF: 0.00519 Hom.: 0

Bravo AF: 0.00217

ExAC AF: 0.000778 AC: 2

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	SIRT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.37
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.11	N
REVEL	Benign	0.076
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.33	T
Polyphen		0.013	B
Vest4		0.15
MVP		0.24
MPC		0.69
ClinPred		0.63	D
GERP RS		0.55
PromoterAI		-0.056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.044
gMVP		0.28
Mutation Taster		=91/9	polymorphism

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: rs548590752; hg19: chr10-69644589;