10-67910388-C-G

Variant names:

• chr10-67910388-C-G
• rs17526356
• NM_012238.5:c.1357+946C>G

Variant summary

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

The NM_012238.5(SIRT1):​c.1357+946C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 151,856 control chromosomes in the GnomAD database, including 20,695 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 0.47 (20695 hom., cov: 31)
• Consequence: SIRT1 NM_012238.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.299
• Publications: 3 publications found

Genes affected

SIRT1 (HGNC:14929): (sirtuin 1) This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class I of the sirtuin family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2008]

SIRT1 Gene-Disease associations (from GenCC):

• autoimmune disease

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• monogenic diabetes

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012238.5. 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
	SIRT1	NM_012238.5	MANE Select	c.1357+946C>G		intron	N/A	NP_036370.2
	SIRT1	NM_001142498.2		c.472+946C>G		intron	N/A	NP_001135970.1	E9PC49
	SIRT1	NM_001314049.2		c.448+946C>G		intron	N/A	NP_001300978.1	B0QZ35

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT1	ENST00000212015.11	TSL:1 MANE Select	c.1357+946C>G		intron	N/A	ENSP00000212015.6	Q96EB6-1
	SIRT1	ENST00000403579.1	TSL:1	c.448+946C>G		intron	N/A	ENSP00000384063.1	B0QZ35
	SIRT1	ENST00000923649.1		c.1576+946C>G		intron	N/A	ENSP00000593708.1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71192 AN: 151756 Hom.: 20699 Cov.: 31

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.506

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.469 AC: 71180 AN: 151856 Hom.: 20695 Cov.: 31 AF XY: 0.465 AC XY: 34511 AN XY: 74204

African (AFR) AF: 0.138 AC: 5728 AN: 41416

American (AMR) AF: 0.504 AC: 7687 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2326 AN: 3470

East Asian (EAS) AF: 0.149 AC: 770 AN: 5152

South Asian (SAS) AF: 0.441 AC: 2121 AN: 4808

European-Finnish (FIN) AF: 0.584 AC: 6151 AN: 10536

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44703 AN: 67908

Other (OTH) AF: 0.510 AC: 1076 AN: 2110

Alfa AF: 0.547 Hom.: 3093

Bravo AF: 0.444

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.49
PhyloP100		0.30
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

Other links and lift over

dbSNP: rs17526356; hg19: chr10-69670145;