10-67885828-T-C

Variant names:

• chr10-67885828-T-C
• rs10997860
• NM_012238.5:c.430+677T>C

Variant summary

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

The NM_012238.5(SIRT1):​c.430+677T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 151,950 control chromosomes in the GnomAD database, including 30,653 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 0.63 (30653 hom., cov: 31)
• Consequence: SIRT1 NM_012238.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 12 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.673 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.430+677T>C		intron	N/A	NP_036370.2
	SIRT1	NM_001142498.2		c.-214+429T>C		intron	N/A	NP_001135970.1	E9PC49
	SIRT1	NM_001314049.2		c.-605+429T>C		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.430+677T>C		intron	N/A	ENSP00000212015.6	Q96EB6-1
	SIRT1	ENST00000923649.1		c.430+677T>C		intron	N/A	ENSP00000593708.1
	SIRT1	ENST00000959939.1		c.430+677T>C		intron	N/A	ENSP00000629998.1

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95103 AN: 151832 Hom.: 30632 Cov.: 31

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.527

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.590

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.624

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

GnomAD4 genome AF: 0.626 AC: 95164 AN: 151950 Hom.: 30653 Cov.: 31 AF XY: 0.617 AC XY: 45808 AN XY: 74256

African (AFR) AF: 0.649 AC: 26864 AN: 41420

American (AMR) AF: 0.570 AC: 8690 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2359 AN: 3464

East Asian (EAS) AF: 0.151 AC: 781 AN: 5178

South Asian (SAS) AF: 0.454 AC: 2191 AN: 4824

European-Finnish (FIN) AF: 0.590 AC: 6208 AN: 10526

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.678 AC: 46085 AN: 67984

Other (OTH) AF: 0.627 AC: 1320 AN: 2104

Alfa AF: 0.653 Hom.: 4735

Bravo AF: 0.622

Asia WGS AF: 0.389 AC: 1356 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.49
PhyloP100		-1.2
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: rs10997860; hg19: chr10-69645586;