Genetic Variant SIRT6:c.66+411A>G (chr19-4182063-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_016539.4(SIRT6):c.66+411A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 169,270 control chromosomes in the GnomAD database, including 1,723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1564 hom., cov: 32)

Exomes 𝑓: 0.11 ( 159 hom. )

Consequence

SIRT6
NM_016539.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.41

Publications

24 publications found

Variant links:

Genes affected

SIRT6 (HGNC:14934): (sirtuin 6) This gene encodes a member of the sirtuin family of NAD-dependent enzymes that are implicated in cellular stress resistance, genomic stability, aging and energy homeostasis. The encoded protein is localized to the nucleus, exhibits ADP-ribosyl transferase and histone deacetylase activities, and plays a role in DNA repair, maintenance of telomeric chromatin, inflammation, lipid and glucose metabolism. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

SIRT6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016539.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SIRT6	NM_016539.4	MANE Select	c.66+411A>G	intron	N/A	NP_057623.2
SIRT6	NM_001193285.3		c.66+411A>G	intron	N/A	NP_001180214.1
SIRT6	NM_001321059.2		c.66+411A>G	intron	N/A	NP_001307988.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SIRT6	ENST00000337491.7	TSL:1 MANE Select	c.66+411A>G	intron	N/A	ENSP00000337332.1
SIRT6	ENST00000305232.10	TSL:1	c.66+411A>G	intron	N/A	ENSP00000305310.5
SIRT6	ENST00000599365.5	TSL:1	n.66+411A>G	intron	N/A	ENSP00000473085.1

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18721

AN:

151854

Hom.:

1564

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0658

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.221

Gnomad ASJ

AF:

0.134

Gnomad EAS

AF:

0.361

Gnomad SAS

AF:

0.0935

Gnomad FIN

AF:

0.149

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.118

GnomAD4 exome

AF:

0.112

AC:

1941

AN:

17296

Hom.:

159

AF XY:

0.110

AC XY:

1026

AN XY:

9340

show subpopulations

African (AFR)

AF:

0.0635

AC:

AN:

520

American (AMR)

AF:

0.205

AC:

AN:

386

Ashkenazi Jewish (ASJ)

AF:

0.122

AC:

AN:

616

East Asian (EAS)

AF:

0.322

AC:

316

AN:

980

South Asian (SAS)

AF:

0.0673

AC:

143

AN:

2124

European-Finnish (FIN)

AF:

0.110

AC:

AN:

746

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

European-Non Finnish (NFE)

AF:

0.100

AC:

1083

AN:

10784

Other (OTH)

AF:

0.119

AC:

124

AN:

1042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

169

253

338

422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.123

AC:

18734

AN:

151974

Hom.:

1564

Cov.:

AF XY:

0.128

AC XY:

9511

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.0659

AC:

2732

AN:

41464

American (AMR)

AF:

0.221

AC:

3377

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

464

AN:

3468

East Asian (EAS)

AF:

0.360

AC:

1843

AN:

5124

South Asian (SAS)

AF:

0.0938

AC:

452

AN:

4820

European-Finnish (FIN)

AF:

0.149

AC:

1578

AN:

10566

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.116

AC:

7864

AN:

67958

Other (OTH)

AF:

0.119

AC:

252

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

796

1592

2387

3183

3979

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

198

396

594

792

990

<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:

0.119

Hom.:

5055

Bravo

AF:

0.126

Asia WGS

AF:

0.213

AC:

740

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.2

(source)

DANN

Benign

0.87

PhyloP100

-2.4

PromoterAI

0.059

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over