dbSNP rs1202064844: SIRT1:p.Ser26Thr (chr10-67884797-T-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_012238.5(SIRT1):c.76T>A(p.Ser26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,116,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 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 0.000021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

SIRT1
NM_012238.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.21

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=0.18027937).

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT1	NM_012238.5 link	c.76T>A	p.Ser26Thr	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.76T>A	p.Ser26Thr	missense_variant	Exon 1 of 9	1	NM_012238.5	ENSP00000212015.6		Q96EB6-1

Frequencies

GnomAD3 genomes

AF:

0.0000206

AC:

AN:

145880

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000455

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000237

AC:

AN:

970312

Hom.:

Cov.:

AF XY:

0.0000328

AC XY:

AN XY:

457700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20040

American (AMR)

AF:

0.00

AC:

AN:

6452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11652

East Asian (EAS)

AF:

0.00

AC:

AN:

22826

South Asian (SAS)

AF:

0.00

AC:

AN:

17728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2508

European-Non Finnish (NFE)

AF:

0.0000262

AC:

AN:

838928

Other (OTH)

AF:

0.0000264

AC:

AN:

37814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.534

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000206

AC:

AN:

145880

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

71112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40008

American (AMR)

AF:

0.00

AC:

AN:

14756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3390

East Asian (EAS)

AF:

0.00

AC:

AN:

4428

South Asian (SAS)

AF:

0.00

AC:

AN:

4112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000455

AC:

AN:

65914

Other (OTH)

AF:

0.00

AC:

AN:

2032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.21

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.43

M_CAP

Benign

0.079

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

PhyloP100

1.2

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.38

REVEL

Benign

0.052

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.034

Polyphen

0.78

Vest4

0.14

MutPred

0.13

Gain of relative solvent accessibility (P = 0.0082);

MVP

0.31

MPC

0.29

ClinPred

0.22

GERP RS

2.5

PromoterAI

-0.0058

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.24

Mutation Taster

=90/10

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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rs1202064844

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