Genetic Variant NM_012238.5:c.220_222delGCG (chr10-67884928-TGCG-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_012238.5(SIRT1):c.220_222delGCG(p.Ala74del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000376 in 1,090,178 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

SIRT1
NM_012238.5 conservative_inframe_deletion

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 -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_012238.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT1	NM_012238.5 link	c.220_222delGCG	p.Ala74del	conservative_inframe_deletion	Exon 1 of 9	ENST00000212015.11	NP_036370.2	Q96EB6-1A0A024QZQ1
SIRT1	NM_001142498.2 link	c.-684_-682delGCG		upstream_gene_variant			NP_001135970.1	Q96EB6A8K128E9PC49
SIRT1	NM_001314049.2 link	c.-1075_-1073delGCG		upstream_gene_variant			NP_001300978.1	Q96EB6B0QZ35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIRT1	ENST00000212015.11 link	c.220_222delGCG	p.Ala74del	conservative_inframe_deletion	Exon 1 of 9	1	NM_012238.5	ENSP00000212015.6	Q96EB6-1
SIRT1	ENST00000432464.5 link	c.-684_-682delGCG		upstream_gene_variant		5		ENSP00000409208.1	E9PC49
SIRT1	ENST00000497639.5 link	n.-252_-250delGCG		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

3024

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1090178

Hom.:

AF XY:

0.0000482

AC XY:

AN XY:

518470

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22294

American (AMR)

AF:

0.00

AC:

AN:

8162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14046

East Asian (EAS)

AF:

0.0000379

AC:

AN:

26380

South Asian (SAS)

AF:

0.000242

AC:

AN:

20680

European-Finnish (FIN)

AF:

0.0000746

AC:

AN:

26810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3220

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

925076

Other (OTH)

AF:

0.0000689

AC:

AN:

43510

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.249

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=83/17

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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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