Genetic Variant SIRT1:p.Leu107Pro (chr10-67885041-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012238.5(SIRT1):c.320T>C(p.Leu107Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. L107L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SIRT1
NM_012238.5 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.148

Publications

10 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 Gene-Disease associations (from GenCC):

autoimmune disease
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
monogenic diabetes
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

SIRT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIRT1	NM_012238.5	MANE Select	c.320T>C	p.Leu107Pro	missense	Exon 1 of 9	NP_036370.2
SIRT1	NM_001142498.2		c.-572T>C		upstream_gene	N/A	NP_001135970.1	E9PC49
SIRT1	NM_001314049.2		c.-963T>C		upstream_gene	N/A	NP_001300978.1	B0QZ35

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIRT1	ENST00000212015.11	TSL:1 MANE Select	c.320T>C	p.Leu107Pro	missense	Exon 1 of 9	ENSP00000212015.6	Q96EB6-1
SIRT1	ENST00000923649.1		c.320T>C	p.Leu107Pro	missense	Exon 1 of 10	ENSP00000593708.1
SIRT1	ENST00000959939.1		c.320T>C	p.Leu107Pro	missense	Exon 1 of 9	ENSP00000629998.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1264734

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

619832

African (AFR)

AF:

0.00

AC:

AN:

25442

American (AMR)

AF:

0.00

AC:

AN:

19090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20096

East Asian (EAS)

AF:

0.00

AC:

AN:

27596

South Asian (SAS)

AF:

0.00

AC:

AN:

63344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5112

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1008858

Other (OTH)

AF:

0.00

AC:

AN:

50944

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Variant of unknown significance (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.29

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.35

M_CAP

Pathogenic

0.79

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.20

PhyloP100

0.15

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.2

REVEL

Benign

0.23

Sift

Benign

0.13

Sift4G

Benign

0.23

Polyphen

0.0010

Vest4

0.71

MutPred

0.22

Gain of glycosylation at P110 (P = 0.0656)

MVP

0.76

MPC

0.40

ClinPred

0.096

GERP RS

1.1

PromoterAI

-0.093

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.33

Mutation Taster

=23/77

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over