Variant 10-67884864-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012238.5(SIRT1):c.143C>T(p.Pro48Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,216,858 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000060 ( 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: 0.883

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043519914).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRT1	NM_012238.5 linkuse as main transcript	c.143C>T	p.Pro48Leu	missense_variant	1/9	ENST00000212015.11	NP_036370.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIRT1	ENST00000212015.11 linkuse as main transcript	c.143C>T	p.Pro48Leu	missense_variant	1/9	1	NM_012238.5	ENSP00000212015	P1	Q96EB6-1

Frequencies

GnomAD3 genomes

AF:

0.0000663

AC:

AN:

150778

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00197

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:

0.0000216

AC:

AN:

1065978

Hom.:

Cov.:

AF XY:

0.0000218

AC XY:

AN XY:

503456

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000670

Gnomad4 SAS exome

AF:

0.0000515

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000110

Gnomad4 OTH exome

AF:

0.0000235

GnomAD4 genome

AF:

0.0000597

AC:

AN:

150880

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

73696

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00178

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 04, 2022

This variant has not been reported in the literature in individuals affected with SIRT1-related conditions. This variant is present in population databases (rs568432780, gnomAD 0.2%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 48 of the SIRT1 protein (p.Pro48Leu). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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

0.098

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.62

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.044

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

MutationTaster

Benign

0.92

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.38

REVEL

Benign

0.059

Sift

Uncertain

0.0030

Sift4G

Benign

0.10

Polyphen

0.0

Vest4

0.17

MutPred

0.16

Loss of glycosylation at P48 (P = 0.0323);

MVP

0.14

MPC

0.69

ClinPred

0.66

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.039

gMVP

0.22

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