NM_012238.5:c.1451T>A

Variant names:

• chr10-67912567-T-A
• rs1063111
• NM_012238.5:c.1451T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012238.5(SIRT1):​c.1451T>A​(p.Val484Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. V484V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.64
• Publications: 6 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1451T>A	p.Val484Asp	missense	Exon 8 of 9	NP_036370.2
	SIRT1	NM_001142498.2		c.566T>A	p.Val189Asp	missense	Exon 7 of 8	NP_001135970.1	E9PC49
	SIRT1	NM_001314049.2		c.542T>A	p.Val181Asp	missense	Exon 9 of 10	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.1451T>A	p.Val484Asp	missense	Exon 8 of 9	ENSP00000212015.6	Q96EB6-1
	SIRT1	ENST00000403579.1	TSL:1	c.542T>A	p.Val181Asp	missense	Exon 5 of 6	ENSP00000384063.1	B0QZ35
	SIRT1	ENST00000923649.1		c.1670T>A	p.Val557Asp	missense	Exon 9 of 10	ENSP00000593708.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.18
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.24	N
PhyloP100		4.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.23
Sift	Benign	0.33	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.23	B
Vest4		0.79
MutPred		0.17		Loss of catalytic residue at V484 (P = 0.1119)
MVP		0.80
MPC		0.48
ClinPred		0.31	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.88
Mutation Taster		=13/87	disease causing

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: rs1063111; hg19: chr10-69672324;