Variant chr19-4174769-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016539.4(SIRT6):c.916C>T(p.Arg306Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,496,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

SIRT6
NM_016539.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0068581104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRT6	NM_016539.4 link	c.916C>T	p.Arg306Trp	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 link	c.916C>T	p.Arg306Trp	missense_variant	8/8	1	NM_016539.4	ENSP00000337332.1		Q8N6T7-1

Frequencies

GnomAD3 genomes

AF:

0.0000538

AC:

AN:

148834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000743

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000669

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000403

Gnomad SAS

AF:

0.000215

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000498

GnomAD3 exomes

AF:

0.0000367

AC:

AN:

108944

Hom.:

AF XY:

0.0000536

AC XY:

AN XY:

55986

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000443

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000922

Gnomad SAS exome

AF:

0.000142

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000326

AC:

AN:

1347964

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

660286

show subpopulations

Gnomad4 AFR exome

AF:

0.0000321

Gnomad4 AMR exome

AF:

0.0000597

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000563

Gnomad4 SAS exome

AF:

0.0000707

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000312

Gnomad4 OTH exome

AF:

0.0000178

GnomAD4 genome

AF:

0.0000537

AC:

AN:

148942

Hom.:

Cov.:

AF XY:

0.0000826

AC XY:

AN XY:

72620

show subpopulations

Gnomad4 AFR

AF:

0.0000741

Gnomad4 AMR

AF:

0.0000668

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000403

Gnomad4 SAS

AF:

0.000215

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000493

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.000262

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000253

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2024

The c.916C>T (p.R306W) alteration is located in exon 8 (coding exon 8) of the SIRT6 gene. This alteration results from a C to T substitution at nucleotide position 916, causing the arginine (R) at amino acid position 306 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.067

MetaRNN

Benign

0.0069

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;L;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.67

N;N;.

REVEL

Benign

0.097

Sift

Benign

0.085

T;T;.

Sift4G

Benign

0.069

T;T;.

Polyphen

0.83

P;P;.

Vest4

0.11

MVP

0.29

MPC

0.57

ClinPred

0.056

GERP RS

1.4

Varity_R

0.083

gMVP

0.29

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