19-4174953-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_016539.4(SIRT6):c.739-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.876 in 1,609,346 control chromosomes in the GnomAD database, including 618,880 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.88 (59889 hom., cov: 32)
  • Exomes 𝑓: 0.87 (558991 hom.)
• Consequence: SIRT6 NM_016539.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001179
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.285

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-4174953-A-G is Benign according to our data. Variant chr19-4174953-A-G is described in ClinVar as [Benign]. Clinvar id is 1224695.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT6	NM_016539.4	c.739-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000337491.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT6	ENST00000337491.7	c.739-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_016539.4	P1

Frequencies

GnomAD3 genomes AF: 0.884 AC: 134433 AN: 151994 Hom.: 59840 Cov.: 32

Gnomad AFR AF: 0.954

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.866

Gnomad EAS AF: 0.700

Gnomad SAS AF: 0.911

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.885

Gnomad OTH AF: 0.887

GnomAD3 exomes AF: 0.854 AC: 204358 AN: 239388 Hom.: 88086 AF XY: 0.862 AC XY: 113018 AN XY: 131044

Gnomad AFR exome AF: 0.956

Gnomad AMR exome AF: 0.717

Gnomad ASJ exome AF: 0.865

Gnomad EAS exome AF: 0.706

Gnomad SAS exome AF: 0.926

Gnomad FIN exome AF: 0.854

Gnomad NFE exome AF: 0.886

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.875 AC: 1274635 AN: 1457234 Hom.: 558991 Cov.: 69 AF XY: 0.877 AC XY: 635755 AN XY: 725018

Gnomad4 AFR exome AF: 0.961

Gnomad4 AMR exome AF: 0.727

Gnomad4 ASJ exome AF: 0.866

Gnomad4 EAS exome AF: 0.703

Gnomad4 SAS exome AF: 0.922

Gnomad4 FIN exome AF: 0.860

Gnomad4 NFE exome AF: 0.881

Gnomad4 OTH exome AF: 0.870

GnomAD4 genome AF: 0.884 AC: 134543 AN: 152112 Hom.: 59889 Cov.: 32 AF XY: 0.879 AC XY: 65384 AN XY: 74352

Gnomad4 AFR AF: 0.954

Gnomad4 AMR AF: 0.775

Gnomad4 ASJ AF: 0.866

Gnomad4 EAS AF: 0.701

Gnomad4 SAS AF: 0.911

Gnomad4 FIN AF: 0.851

Gnomad4 NFE AF: 0.885

Gnomad4 OTH AF: 0.885

Alfa AF: 0.884 Hom.: 14689

Bravo AF: 0.883

Asia WGS AF: 0.809 AC: 2815 AN: 3478

EpiCase AF: 0.892

EpiControl AF: 0.886

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.7
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.020		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: rs350845; hg19: chr19-4174950; COSMIC: COSV50288376; COSMIC: COSV50288376;