Genetic Variant SIRT1:p.Gly30Arg (chr10-67884809-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_012238.5(SIRT1):c.88G>C(p.Gly30Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000489 in 1,023,122 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

SIRT1
NM_012238.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.28

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:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13081902).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT1	NM_012238.5 link	c.88G>C	p.Gly30Arg	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.88G>C	p.Gly30Arg	missense_variant	Exon 1 of 9	1	NM_012238.5	ENSP00000212015.6		Q96EB6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000489

AC:

AN:

1023122

Hom.:

Cov.:

AF XY:

0.00000208

AC XY:

AN XY:

481400

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21096

American (AMR)

AF:

0.00

AC:

AN:

6590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12088

East Asian (EAS)

AF:

0.00

AC:

AN:

23544

South Asian (SAS)

AF:

0.00

AC:

AN:

18862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13652

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2590

European-Non Finnish (NFE)

AF:

0.00000565

AC:

AN:

884962

Other (OTH)

AF:

0.00

AC:

AN:

39738

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.28

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PhyloP100

1.3

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.66

REVEL

Benign

0.049

Sift

Uncertain

0.0020

Sift4G

Benign

0.14

Polyphen

0.0040

Vest4

0.15

MutPred

0.16

Gain of MoRF binding (P = 0.0166);

MVP

0.16

MPC

0.95

ClinPred

0.48

GERP RS

3.1

PromoterAI

0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.19

Mutation Taster

=92/8

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

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chr10-67884809-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over