Variant 19-4174813-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016539.4(SIRT6):c.872G>A(p.Arg291His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,387,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R291C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000077 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

SIRT6
NM_016539.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24398765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT6	NM_016539.4 linkuse as main transcript	c.872G>A	p.Arg291His	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.872G>A	p.Arg291His	missense_variant	8/8	1	NM_016539.4	P1	Q8N6T7-1

Frequencies

GnomAD3 genomes

AF:

0.0000771

AC:

AN:

38910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000201

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000646

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000855

AC:

AN:

116934

Hom.:

AF XY:

0.0000156

AC XY:

AN XY:

64006

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000282

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1348742

Hom.:

Cov.:

AF XY:

0.0000106

AC XY:

AN XY:

662722

show subpopulations

Gnomad4 AFR exome

AF:

0.0000324

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000423

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000154

Gnomad4 NFE exome

AF:

0.00000283

Gnomad4 OTH exome

AF:

0.0000357

GnomAD4 genome

AF:

0.0000771

AC:

AN:

38910

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

19416

show subpopulations

Gnomad4 AFR

AF:

0.000107

Gnomad4 AMR

AF:

0.000201

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000646

Gnomad4 OTH

AF:

0.00

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

Jul 19, 2022

The c.872G>A (p.R291H) alteration is located in exon 8 (coding exon 8) of the SIRT6 gene. This alteration results from a G to A substitution at nucleotide position 872, causing the arginine (R) at amino acid position 291 to be replaced by a histidine (H). 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

0.10

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.080

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.57

N;N;.

REVEL

Benign

0.077

Sift

Uncertain

0.029

D;T;.

Sift4G

Benign

0.48

T;T;.

Polyphen

0.96

D;D;.

Vest4

0.21

MutPred

0.24

.;Gain of methylation at K296 (P = 0.1064);.;

MVP

0.66

MPC

0.92

ClinPred

0.53

GERP RS

3.5

Varity_R

0.23

gMVP

0.21

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