Variant 19-4174862-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_016539.4(SIRT6):c.823G>A(p.Ala275Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,600,188 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.011 ( 25 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 27 hom. )

Consequence

SIRT6
NM_016539.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.322

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004946083).

BP6

Variant 19-4174862-C-T is Benign according to our data. Variant chr19-4174862-C-T is described in ClinVar as [Benign]. Clinvar id is 777379.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1627/152126) while in subpopulation AFR AF= 0.0359 (1487/41470). AF 95% confidence interval is 0.0343. There are 25 homozygotes in gnomad4. There are 757 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT6	NM_016539.4 linkuse as main transcript	c.823G>A	p.Ala275Thr	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.823G>A	p.Ala275Thr	missense_variant	8/8	1	NM_016539.4	P1	Q8N6T7-1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1623

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00648

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00286

AC:

655

AN:

229228

Hom.:

AF XY:

0.00203

AC XY:

258

AN XY:

126918

show subpopulations

Gnomad AFR exome

AF:

0.0348

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000280

Gnomad SAS exome

AF:

0.000265

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000268

Gnomad OTH exome

AF:

0.00344

GnomAD4 exome

AF:

0.00128

AC:

1860

AN:

1448062

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

794

AN XY:

720754

show subpopulations

Gnomad4 AFR exome

AF:

0.0364

Gnomad4 AMR exome

AF:

0.00331

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000217

Gnomad4 OTH exome

AF:

0.00326

GnomAD4 genome

AF:

0.0107

AC:

1627

AN:

152126

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

757

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0359

Gnomad4 AMR

AF:

0.00647

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.0121

ESP6500AA

AF:

0.0314

AC:

133

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.00307

AC:

367

Asia WGS

AF:

0.00404

AC:

AN:

3476

EpiCase

AF:

0.000218

EpiControl

AF:

0.000416

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.0050

DANN

Benign

0.97

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.54

T;T;T

MetaRNN

Benign

0.0049

T;T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.52

N;N;.

REVEL

Benign

0.032

Sift

Benign

0.39

T;T;.

Sift4G

Benign

0.45

T;T;.

Polyphen

0.0020

B;B;.

Vest4

0.035

MVP

0.19

MPC

0.35

ClinPred

0.011

GERP RS

-0.79

Varity_R

0.11

gMVP

0.18

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