rs201230502

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_012238.5(SIRT1):c.40T>C(p.Ser14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,225,138 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0023 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 7 hom. )

Consequence

SIRT1
NM_012238.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 1.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity SIR1_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0050804913).

BS2

High AC in GnomAd4 at 348 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT1	NM_012238.5 link	c.40T>C	p.Ser14Pro	missense_variant	Exon 1 of 9	ENST00000212015.11	NP_036370.2	Q96EB6-1A0A024QZQ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRT1	ENST00000212015.11 link	c.40T>C	p.Ser14Pro	missense_variant	Exon 1 of 9	1	NM_012238.5	ENSP00000212015.6		Q96EB6-1

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

348

AN:

150770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000925

Gnomad AMI

AF:

0.0684

Gnomad AMR

AF:

0.00250

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00230

Gnomad FIN

AF:

0.0000962

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00285

Gnomad OTH

AF:

0.00242

GnomAD4 exome

AF:

0.00306

AC:

3285

AN:

1074260

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

1539

AN XY:

507230

show subpopulations

Gnomad4 AFR exome

AF:

0.000353

Gnomad4 AMR exome

AF:

0.00133

Gnomad4 ASJ exome

AF:

0.0000708

Gnomad4 EAS exome

AF:

0.0000382

Gnomad4 SAS exome

AF:

0.00191

Gnomad4 FIN exome

AF:

0.000144

Gnomad4 NFE exome

AF:

0.00338

Gnomad4 OTH exome

AF:

0.00275

GnomAD4 genome

AF:

0.00231

AC:

348

AN:

150878

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

151

AN XY:

73654

show subpopulations

Gnomad4 AFR

AF:

0.000922

Gnomad4 AMR

AF:

0.00249

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00230

Gnomad4 FIN

AF:

0.0000962

Gnomad4 NFE

AF:

0.00285

Gnomad4 OTH

AF:

0.00239

Alfa

AF:

0.00221

Hom.:

Bravo

AF:

0.00266

ExAC

AF:

0.000490

AC:

Asia WGS

AF:

0.000586

AC:

AN:

3428

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 14 of the SIRT1 protein (p.Ser14Pro). This variant is present in population databases (rs201230502, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SIRT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1524941). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

SIRT1-related disorder

Benign:1

Jun 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.26

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.42

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.0051

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.63

REVEL

Benign

0.048

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.053

Polyphen

0.0

Vest4

0.26

MVP

0.29

MPC

0.48

ClinPred

0.35

GERP RS

-0.62

Varity_R

0.26

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over