Genetic Variant NM_012238.5:c.109C>G (chr10-67884830-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012238.5(SIRT1):c.109C>G(p.Pro37Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,071,198 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. P37L) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

SIRT1
NM_012238.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23

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 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13752368).

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.109C>G	p.Pro37Ala	missense	Exon 1 of 9	NP_036370.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIRT1	ENST00000212015.11	TSL:1 MANE Select	c.109C>G	p.Pro37Ala	missense	Exon 1 of 9	ENSP00000212015.6	Q96EB6-1
SIRT1	ENST00000923649.1		c.109C>G	p.Pro37Ala	missense	Exon 1 of 10	ENSP00000593708.1
SIRT1	ENST00000959939.1		c.109C>G	p.Pro37Ala	missense	Exon 1 of 9	ENSP00000629998.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000373

AC:

AN:

1071198

Hom.:

Cov.:

AF XY:

0.00000395

AC XY:

AN XY:

505738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22544

American (AMR)

AF:

0.00

AC:

AN:

8084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13912

East Asian (EAS)

AF:

0.000154

AC:

AN:

25982

South Asian (SAS)

AF:

0.00

AC:

AN:

19434

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2860

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

914442

Other (OTH)

AF:

0.00

AC:

AN:

43016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.18

Eigen

Benign

-0.099

Eigen_PC

Benign

-0.026

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.54

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

2.2

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.090

REVEL

Benign

0.069

Sift

Benign

0.045

Sift4G

Benign

0.50

Polyphen

0.23

Vest4

0.17

MutPred

0.26

Loss of glycosylation at P37 (P = 0.0113)

MVP

0.22

MPC

0.53

ClinPred

0.37

GERP RS

3.9

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.066

gMVP

0.18

Mutation Taster

=85/15

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over