19-4177054-A-G

Variant names:

• chr19-4177054-A-G
• rs350844
• NM_016539.4:c.437+25T>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.437+25T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 1,606,110 control chromosomes in the GnomAD database, including 617,161 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.

• Frequency:
  • Genomes: 𝑓 0.89 (59671 hom., cov: 27)
  • Exomes 𝑓: 0.87 (557490 hom.)
• Consequence: SIRT6 NM_016539.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.09
• Publications: 27 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: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.946 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT6	NM_016539.4	MANE Select	c.437+25T>C		intron	N/A	NP_057623.2	Q8N6T7-1
	SIRT6	NM_001193285.3		c.437+25T>C		intron	N/A	NP_001180214.1	Q8N6T7-2
	SIRT6	NM_001321059.2		c.254+25T>C		intron	N/A	NP_001307988.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT6	ENST00000337491.7	TSL:1 MANE Select	c.437+25T>C		intron	N/A	ENSP00000337332.1	Q8N6T7-1
	SIRT6	ENST00000305232.10	TSL:1	c.437+25T>C		intron	N/A	ENSP00000305310.5	Q8N6T7-2
	SIRT6	ENST00000599365.5	TSL:1	n.*177+25T>C		intron	N/A	ENSP00000473085.1	M0R0B2

Frequencies

GnomAD3 genomes AF: 0.885 AC: 133996 AN: 151352 Hom.: 59623 Cov.: 27

Gnomad AFR AF: 0.954

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.778

Gnomad ASJ AF: 0.866

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.911

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.885

Gnomad OTH AF: 0.887

GnomAD2 exomes AF: 0.855 AC: 210605 AN: 246376 AF XY: 0.863

Gnomad AFR exome AF: 0.956

Gnomad AMR exome AF: 0.718

Gnomad ASJ exome AF: 0.865

Gnomad EAS exome AF: 0.707

Gnomad FIN exome AF: 0.855

Gnomad NFE exome AF: 0.886

Gnomad OTH exome AF: 0.861

GnomAD4 exome AF: 0.874 AC: 1271906 AN: 1454640 Hom.: 557490 Cov.: 29 AF XY: 0.877 AC XY: 634237 AN XY: 723540

African (AFR) AF: 0.961 AC: 32040 AN: 33350

American (AMR) AF: 0.727 AC: 32146 AN: 44198

Ashkenazi Jewish (ASJ) AF: 0.866 AC: 22489 AN: 25972

East Asian (EAS) AF: 0.704 AC: 27773 AN: 39452

South Asian (SAS) AF: 0.922 AC: 78997 AN: 85634

European-Finnish (FIN) AF: 0.860 AC: 45599 AN: 53042

Middle Eastern (MID) AF: 0.934 AC: 5325 AN: 5702

European-Non Finnish (NFE) AF: 0.881 AC: 975261 AN: 1107206

Other (OTH) AF: 0.870 AC: 52276 AN: 60084

GnomAD4 genome AF: 0.885 AC: 134104 AN: 151470 Hom.: 59671 Cov.: 27 AF XY: 0.881 AC XY: 65129 AN XY: 73946

African (AFR) AF: 0.954 AC: 39467 AN: 41374

American (AMR) AF: 0.777 AC: 11805 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.866 AC: 3006 AN: 3472

East Asian (EAS) AF: 0.709 AC: 3564 AN: 5026

South Asian (SAS) AF: 0.911 AC: 4376 AN: 4802

European-Finnish (FIN) AF: 0.854 AC: 8971 AN: 10502

Middle Eastern (MID) AF: 0.942 AC: 275 AN: 292

European-Non Finnish (NFE) AF: 0.885 AC: 60025 AN: 67804

Other (OTH) AF: 0.885 AC: 1860 AN: 2102

Alfa AF: 0.886 Hom.: 94590

Bravo AF: 0.883

Asia WGS AF: 0.809 AC: 2815 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.013
DANN	Benign	0.21
PhyloP100		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs350844;

hg19: chr19-4177051;