19-4175788-T-G

Variant names:

• chr19-4175788-T-G
• rs7246235
• NM_016539.4:c.534-28A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016539.4(SIRT6):​c.534-28A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 1,555,682 control chromosomes in the GnomAD database, including 3,218 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.070 (824 hom., cov: 33)
  • Exomes 𝑓: 0.027 (2394 hom.)
• Consequence: SIRT6 NM_016539.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.104
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016539.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT6	NM_016539.4	MANE Select	c.534-28A>C		intron	N/A	NP_057623.2
	SIRT6	NM_001193285.3		c.533+54A>C		intron	N/A	NP_001180214.1
	SIRT6	NM_001321059.2		c.351-28A>C		intron	N/A	NP_001307988.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT6	ENST00000337491.7	TSL:1 MANE Select	c.534-28A>C		intron	N/A	ENSP00000337332.1
	SIRT6	ENST00000305232.10	TSL:1	c.533+54A>C		intron	N/A	ENSP00000305310.5
	SIRT6	ENST00000599365.5	TSL:1	n.*273+54A>C		intron	N/A	ENSP00000473085.1

Frequencies

GnomAD3 genomes AF: 0.0693 AC: 10545 AN: 152080 Hom.: 820 Cov.: 33

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.00934

Gnomad OTH AF: 0.0626

GnomAD2 exomes AF: 0.0611 AC: 9717 AN: 158988 AF XY: 0.0631

Gnomad AFR exome AF: 0.176

Gnomad AMR exome AF: 0.0521

Gnomad ASJ exome AF: 0.0454

Gnomad EAS exome AF: 0.211

Gnomad FIN exome AF: 0.00295

Gnomad NFE exome AF: 0.00964

Gnomad OTH exome AF: 0.0393

GnomAD4 exome AF: 0.0274 AC: 38470 AN: 1403484 Hom.: 2394 Cov.: 32 AF XY: 0.0301 AC XY: 20878 AN XY: 692804

African (AFR) AF: 0.179 AC: 5742 AN: 32010

American (AMR) AF: 0.0478 AC: 1726 AN: 36140

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 1179 AN: 24896

East Asian (EAS) AF: 0.201 AC: 7336 AN: 36436

South Asian (SAS) AF: 0.132 AC: 10500 AN: 79386

European-Finnish (FIN) AF: 0.00247 AC: 122 AN: 49404

Middle Eastern (MID) AF: 0.0537 AC: 300 AN: 5588

European-Non Finnish (NFE) AF: 0.00821 AC: 8876 AN: 1081550

Other (OTH) AF: 0.0463 AC: 2689 AN: 58074

GnomAD4 genome AF: 0.0696 AC: 10587 AN: 152198 Hom.: 824 Cov.: 33 AF XY: 0.0726 AC XY: 5405 AN XY: 74418

African (AFR) AF: 0.175 AC: 7273 AN: 41534

American (AMR) AF: 0.0421 AC: 643 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 177 AN: 3472

East Asian (EAS) AF: 0.202 AC: 1041 AN: 5158

South Asian (SAS) AF: 0.134 AC: 649 AN: 4830

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10610

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.00935 AC: 636 AN: 67988

Other (OTH) AF: 0.0643 AC: 136 AN: 2116

Alfa AF: 0.0220 Hom.: 138

Bravo AF: 0.0768

Asia WGS AF: 0.176 AC: 613 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	6.6
DANN	Benign	0.40
PhyloP100		-0.10
BranchPoint Hunter		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs7246235; hg19: chr19-4175785; COSMIC: COSV50201112; COSMIC: COSV50201112;