10-67916540-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_012238.5(SIRT1):c.2191A>G(p.Ile731Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,614,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SIRT1
NM_012238.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.54

Publications

6 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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023343265).

BP6

Variant 10-67916540-A-G is Benign according to our data. Variant chr10-67916540-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2058577.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 128 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SIRT1	NM_012238.5 link	c.2191A>G	p.Ile731Val	missense_variant	Exon 9 of 9	ENST00000212015.11	NP_036370.2
SIRT1	NM_001142498.2 link	c.1306A>G	p.Ile436Val	missense_variant	Exon 8 of 8		NP_001135970.1
SIRT1	NM_001314049.2 link	c.1282A>G	p.Ile428Val	missense_variant	Exon 10 of 10		NP_001300978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SIRT1	ENST00000212015.11 link	c.2191A>G	p.Ile731Val	missense_variant	Exon 9 of 9	1	NM_012238.5	ENSP00000212015.6
SIRT1	ENST00000403579.1 link	c.1282A>G	p.Ile428Val	missense_variant	Exon 6 of 6	1		ENSP00000384063.1
SIRT1	ENST00000432464.5 link	c.1306A>G	p.Ile436Val	missense_variant	Exon 8 of 8	5		ENSP00000409208.1
SIRT1	ENST00000406900.5 link	c.1282A>G	p.Ile428Val	missense_variant	Exon 7 of 7	2		ENSP00000384508.1

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000247

AC:

AN:

251028

AF XY:

0.000192

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1461810

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.00403

AC:

135

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111964

Other (OTH)

AF:

0.000149

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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

AF:

0.000840

AC:

128

AN:

152336

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00293

AC:

122

AN:

41578

American (AMR)

AF:

0.000196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000361

Hom.:

Bravo

AF:

0.000979

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.0040

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.20

T;T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.54

T;T;.;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.84

L;.;.;.

PhyloP100

-1.5

PrimateAI

Benign

0.26

PROVEAN

Benign

0.20

N;N;N;N

REVEL

Benign

0.030

Sift

Benign

0.33

T;T;T;T

Sift4G

Benign

0.99

T;T;T;T

Vest4

0.023

ClinPred

0.018

GERP RS

-2.4

Varity_R

0.019

gMVP

0.078

Mutation Taster

=88/12

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over