Genetic Variant NM_016539.4:c.438-151A>G (chr19-4176088-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.438-151A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 624,604 control chromosomes in the GnomAD database, including 239,459 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 0.88 ( 59864 hom., cov: 31)

Exomes 𝑓: 0.87 ( 179595 hom. )

Consequence

SIRT6
NM_016539.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.47

Publications

42 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=-1.03).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT6	NM_016539.4 link	c.438-151A>G		intron_variant	Intron 4 of 7	ENST00000337491.7	NP_057623.2	Q8N6T7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRT6	ENST00000337491.7 link	c.438-151A>G		intron_variant	Intron 4 of 7	1	NM_016539.4	ENSP00000337332.1		Q8N6T7-1

Frequencies

GnomAD3 genomes

AF:

0.884

AC:

134417

AN:

152030

Hom.:

59820

Cov.:

show subpopulations

Gnomad AFR

AF:

0.953

Gnomad AMI

AF:

0.829

Gnomad AMR

AF:

0.775

Gnomad ASJ

AF:

0.866

Gnomad EAS

AF:

0.699

Gnomad SAS

AF:

0.911

Gnomad FIN

AF:

0.850

Gnomad MID

AF:

0.943

Gnomad NFE

AF:

0.885

Gnomad OTH

AF:

0.888

GnomAD4 exome

AF:

0.870

AC:

410842

AN:

472456

Hom.:

179595

AF XY:

0.874

AC XY:

216219

AN XY:

247390

show subpopulations

African (AFR)

AF:

0.955

AC:

12566

AN:

13156

American (AMR)

AF:

0.745

AC:

15708

AN:

21076

Ashkenazi Jewish (ASJ)

AF:

0.863

AC:

12149

AN:

14080

East Asian (EAS)

AF:

0.702

AC:

21291

AN:

30326

South Asian (SAS)

AF:

0.923

AC:

42752

AN:

46340

European-Finnish (FIN)

AF:

0.862

AC:

25593

AN:

29704

Middle Eastern (MID)

AF:

0.934

AC:

2111

AN:

2260

European-Non Finnish (NFE)

AF:

0.884

AC:

255330

AN:

288728

Other (OTH)

AF:

0.871

AC:

23342

AN:

26786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

2556

5111

7667

10222

12778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1458

2916

4374

5832

7290

<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:

0.884

AC:

134522

AN:

152148

Hom.:

59864

Cov.:

AF XY:

0.879

AC XY:

65366

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.953

AC:

39576

AN:

41532

American (AMR)

AF:

0.775

AC:

11851

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.866

AC:

3004

AN:

3468

East Asian (EAS)

AF:

0.701

AC:

3605

AN:

5144

South Asian (SAS)

AF:

0.911

AC:

4395

AN:

4822

European-Finnish (FIN)

AF:

0.850

AC:

9002

AN:

10590

Middle Eastern (MID)

AF:

0.939

AC:

276

AN:

294

European-Non Finnish (NFE)

AF:

0.885

AC:

60188

AN:

67980

Other (OTH)

AF:

0.886

AC:

1869

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

774

1547

2321

3094

3868

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

900

1800

2700

3600

4500

<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:

0.882

Hom.:

77597

Bravo

AF:

0.883

Asia WGS

AF:

0.809

AC:

2814

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.0080

(source)

DANN

Benign

0.14

PhyloP100

-5.5

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over