Genetic Variant NM_012238.5:c.217_222dupGCGGCG (chr10-67884928-T-TGCGGCG) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_012238.5(SIRT1):c.217_222dupGCGGCG(p.Ala73_Ala74dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000567 in 1,235,292 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000046 ( 0 hom. )

Consequence

SIRT1
NM_012238.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.27

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 -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_012238.5

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.217_222dupGCGGCG	p.Ala73_Ala74dup	conservative_inframe_insertion	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.217_222dupGCGGCG	p.Ala73_Ala74dup	conservative_inframe_insertion	Exon 1 of 9	1	NM_012238.5	ENSP00000212015.6		Q96EB6-1

Frequencies

GnomAD3 genomes

AF:

0.0000138

AC:

AN:

144732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000259

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:

0.0000152

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000458

AC:

AN:

1090560

Hom.:

Cov.:

AF XY:

0.00000578

AC XY:

AN XY:

518684

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22294

American (AMR)

AF:

0.00

AC:

AN:

8166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14046

East Asian (EAS)

AF:

0.00

AC:

AN:

26404

South Asian (SAS)

AF:

0.00

AC:

AN:

20690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26838

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3222

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

925368

Other (OTH)

AF:

0.00

AC:

AN:

43532

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

AF:

0.0000138

AC:

AN:

144732

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

70570

show subpopulations

African (AFR)

AF:

0.0000259

AC:

AN:

38542

American (AMR)

AF:

0.00

AC:

AN:

14714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.00

AC:

AN:

4778

South Asian (SAS)

AF:

0.00

AC:

AN:

4504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65886

Other (OTH)

AF:

0.00

AC:

AN:

1988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=82/18

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over