rs1063114

chr10-67912586-T-Achr10-67912586-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_012238.5(SIRT1):c.1470T>A(p.Cys490Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SIRT1 NM_012238.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_012238.5 Downstream stopcodon found after 769 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT1	NM_012238.5	c.1470T>A	p.Cys490Ter	stop_gained	8/9	ENST00000212015.11
SIRT1	NM_001142498.2	c.585T>A	p.Cys195Ter	stop_gained	7/8
SIRT1	NM_001314049.2	c.561T>A	p.Cys187Ter	stop_gained	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT1	ENST00000212015.11	c.1470T>A	p.Cys490Ter	stop_gained	8/9	1	NM_012238.5	P1
SIRT1	ENST00000403579.1	c.561T>A	p.Cys187Ter	stop_gained	5/6	1
SIRT1	ENST00000432464.5	c.585T>A	p.Cys195Ter	stop_gained	7/8	5
SIRT1	ENST00000406900.5	c.561T>A	p.Cys187Ter	stop_gained	6/7	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	37
Dann	Uncertain	0.99
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.98
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1063114; hg19: chr10-69672343;