Variant 19-4174748-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_016539.4(SIRT6):c.937G>T(p.Ala313Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,381,200 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A313T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 28)

Exomes 𝑓: 0.0039 ( 11 hom. )

Consequence

SIRT6
NM_016539.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.499

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003927201).

BP6

Variant 19-4174748-C-A is Benign according to our data. Variant chr19-4174748-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 790378.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT6	NM_016539.4 linkuse as main transcript	c.937G>T	p.Ala313Ser	missense_variant	8/8	ENST00000337491.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT6	ENST00000337491.7 linkuse as main transcript	c.937G>T	p.Ala313Ser	missense_variant	8/8	1	NM_016539.4	P1	Q8N6T7-1

Frequencies

GnomAD3 genomes

AF:

0.00357

AC:

412

AN:

115346

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000949

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00702

Gnomad ASJ

AF:

0.00715

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00716

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00438

Gnomad OTH

AF:

0.00578

GnomAD3 exomes

AF:

0.00242

AC:

248

AN:

102354

Hom.:

AF XY:

0.00236

AC XY:

123

AN XY:

52168

show subpopulations

Gnomad AFR exome

AF:

0.000430

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000157

Gnomad FIN exome

AF:

0.00186

Gnomad NFE exome

AF:

0.00388

Gnomad OTH exome

AF:

0.00290

GnomAD4 exome

AF:

0.00389

AC:

4918

AN:

1265810

Hom.:

Cov.:

AF XY:

0.00385

AC XY:

2373

AN XY:

616706

show subpopulations

Gnomad4 AFR exome

AF:

0.000458

Gnomad4 AMR exome

AF:

0.00257

Gnomad4 ASJ exome

AF:

0.00631

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000292

Gnomad4 FIN exome

AF:

0.00188

Gnomad4 NFE exome

AF:

0.00443

Gnomad4 OTH exome

AF:

0.00350

GnomAD4 genome

AF:

0.00358

AC:

413

AN:

115390

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

184

AN XY:

52758

show subpopulations

Gnomad4 AFR

AF:

0.000948

Gnomad4 AMR

AF:

0.00701

Gnomad4 ASJ

AF:

0.00715

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00716

Gnomad4 NFE

AF:

0.00440

Gnomad4 OTH

AF:

0.00575

Alfa

AF:

0.00236

Hom.:

Bravo

AF:

0.00266

ESP6500AA

AF:

0.000761

AC:

ESP6500EA

AF:

0.00435

AC:

ExAC

AF:

0.000945

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.66

Cadd

Benign

0.39

Dann

Benign

0.84

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.51

T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

0.020

N;N;.

REVEL

Benign

0.0080

Sift

Benign

0.14

T;T;.

Sift4G

Benign

0.25

T;T;.

Polyphen

0.081

B;B;.

Vest4

0.096

MVP

0.17

MPC

0.34

ClinPred

0.00022

GERP RS

-0.51

Varity_R

0.043

gMVP

0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over