Variant 19-4174768-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_016539.4(SIRT6):c.917G>A(p.Arg306Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000914 in 1,258,026 control chromosomes in the GnomAD database, including 1 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 (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000085 ( 1 hom. )

Consequence

SIRT6
NM_016539.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.607

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:

SIRT6 (HGNC:):

SIRT6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.012121379).

BP6

Variant 19-4174768-C-T is Benign according to our data. Variant chr19-4174768-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3318655.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRT6	NM_016539.4 linkuse as main transcript	c.917G>A	p.Arg306Gln	missense_variant	8/8	ENST00000337491.7	NP_057623.2	Q8N6T7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIRT6	ENST00000337491.7 linkuse as main transcript	c.917G>A	p.Arg306Gln	missense_variant	8/8	1	NM_016539.4	ENSP00000337332.1		Q8N6T7-1

Frequencies

GnomAD3 genomes

AF:

0.000168

AC:

AN:

100914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000788

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000160

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00397

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000542

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000159

AC:

AN:

106594

Hom.:

AF XY:

0.000201

AC XY:

AN XY:

54790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00123

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000847

AC:

AN:

1157094

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

563526

show subpopulations

Gnomad4 AFR exome

AF:

0.0000396

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000429

Gnomad4 OTH exome

AF:

0.0000694

GnomAD4 genome

AF:

0.000168

AC:

AN:

100932

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

AN XY:

45518

show subpopulations

Gnomad4 AFR

AF:

0.0000787

Gnomad4 AMR

AF:

0.000160

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00399

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000542

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.000127

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.63

DANN

Benign

0.67

DEOGEN2

Benign

0.089

.;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.55

T;T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.51

.;N;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.34

N;N;.

REVEL

Benign

0.024

Sift

Benign

1.0

T;T;.

Sift4G

Benign

0.76

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.082

MVP

0.18

MPC

0.42

ClinPred

0.0099

GERP RS

-1.5

Varity_R

0.016

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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