NM_012238.5:c.77C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_012238.5(SIRT1):c.77C>T(p.Ser26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,220,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S26A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

SIRT1
NM_012238.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.576

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM1

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

BP4

Computational evidence support a benign effect (MetaRNN=0.21051562).

BS2

High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT1	NM_012238.5 link	c.77C>T	p.Ser26Leu	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.77C>T	p.Ser26Leu	missense_variant	Exon 1 of 9	1	NM_012238.5	ENSP00000212015.6		Q96EB6-1

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000224

AC:

AN:

1070960

Hom.:

Cov.:

AF XY:

0.0000218

AC XY:

AN XY:

505722

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22582

American (AMR)

AF:

0.00

AC:

AN:

8108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14000

East Asian (EAS)

AF:

0.00

AC:

AN:

26152

South Asian (SAS)

AF:

0.00

AC:

AN:

19348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20310

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

2872

European-Non Finnish (NFE)

AF:

0.0000219

AC:

AN:

914590

Other (OTH)

AF:

0.0000698

AC:

AN:

42998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150028

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

73126

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41180

American (AMR)

AF:

0.0000660

AC:

AN:

15156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3418

East Asian (EAS)

AF:

0.00

AC:

AN:

5018

South Asian (SAS)

AF:

0.00

AC:

AN:

4738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

300

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66796

Other (OTH)

AF:

0.00

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 01, 2024

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 leucine, which is neutral and non-polar, at codon 26 of the SIRT1 protein (p.Ser26Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. 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: 2082562). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

0.074

Eigen_PC

Benign

0.048

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.68

M_CAP

Benign

0.077

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

PhyloP100

0.58

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.56

REVEL

Benign

0.066

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.011

Polyphen

0.96

Vest4

0.19

MutPred

0.18

Loss of phosphorylation at S26 (P = 0.0062);

MVP

0.25

MPC

0.37

ClinPred

0.58

GERP RS

4.1

PromoterAI

-0.0014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.28

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_012238.5:c.77C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over