19-4174761-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_016539.4(SIRT6):c.924C>G(p.Asn308Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,487,554 control chromosomes in the GnomAD database, including 13 homozygotes. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 28)
  • Exomes 𝑓: 0.0037 (11 hom.)
• Consequence: SIRT6 NM_016539.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.55

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055396855).
• BP6: Variant 19-4174761-G-C is Benign according to our data. Variant chr19-4174761-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 790379.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	c.924C>G	p.Asn308Lys	missense_variant	8/8	ENST00000337491.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT6	ENST00000337491.7	c.924C>G	p.Asn308Lys	missense_variant	8/8	1	NM_016539.4	P1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 406 AN: 143532 Hom.: 2 Cov.: 28

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00402

Gnomad ASJ AF: 0.00668

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00331

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00460

GnomAD3 exomes AF: 0.00252 AC: 266 AN: 105360 Hom.: 0 AF XY: 0.00236 AC XY: 127 AN XY: 53856

Gnomad AFR exome AF: 0.000427

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00591

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000149

Gnomad FIN exome AF: 0.00178

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.00368 AC: 4952 AN: 1343928 Hom.: 11 Cov.: 34 AF XY: 0.00364 AC XY: 2394 AN XY: 657366

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.00247

Gnomad4 ASJ exome AF: 0.00552

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000286

Gnomad4 FIN exome AF: 0.00165

Gnomad4 NFE exome AF: 0.00423

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.00283 AC: 407 AN: 143626 Hom.: 2 Cov.: 28 AF XY: 0.00263 AC XY: 182 AN XY: 69142

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00401

Gnomad4 ASJ AF: 0.00668

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00331

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.00455

Alfa AF: 0.00170 Hom.: 2

Bravo AF: 0.00265

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00311 AC: 12

ExAC AF: 0.00106 AC: 86

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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	0.099
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.19
Dann	Benign	0.85
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.45	T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.15	N;N;.
REVEL	Benign	0.022
Sift	Benign	0.065	T;T;.
Sift4G	Benign	0.42	T;T;.
Polyphen		0.0040	B;B;.
Vest4		0.15
MutPred		0.29		.;Gain of ubiquitination at N308 (P = 0.0048);.;
MVP		0.21
MPC		0.50
ClinPred		0.00084	T
GERP RS		-3.2
Varity_R		0.045
gMVP		0.17

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

Other links and lift over

dbSNP: rs201141490; hg19: chr19-4174758; COSMIC: COSV50186598; COSMIC: COSV50186598;