chr19-4174862-C-T

Position:

• chr19-4174862-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.322

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
SIRT6	NM_016539.4	c.823G>A	p.Ala275Thr	missense_variant	8/8	ENST00000337491.7	NP_057623.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIRT6	ENST00000337491.7	c.823G>A	p.Ala275Thr	missense_variant	8/8	1	NM_016539.4	ENSP00000337332.1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1623 AN: 152012 Hom.: 25 Cov.: 32

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.: 10 AF XY: 0.00203 AC XY: 258 AN XY: 126918

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.: 27 Cov.: 68 AF XY: 0.00110 AC XY: 794 AN XY: 720754

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.: 25 Cov.: 32 AF XY: 0.0102 AC XY: 757 AN XY: 74366

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.: 6

Bravo AF: 0.0121

ESP6500AA AF: 0.0314 AC: 133

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00307 AC: 367

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000416

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0050
DANN	Benign	0.97
DEOGEN2	Benign	0.081	.;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.54	T;T;T
MetaRNN	Benign	0.0049	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	.;M;.
PrimateAI	Uncertain	0.49	T
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	T
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

Other links and lift over

dbSNP: rs74317014; hg19: chr19-4174859; COSMIC: COSV50225203; COSMIC: COSV50225203;