NM_012238.5:c.76T>G

Variant names:

• chr10-67884797-T-G
• rs1202064844
• NM_012238.5:c.76T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012238.5(SIRT1):​c.76T>G​(p.Ser26Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S26L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1222904).

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.76T>G	p.Ser26Ala	missense	Exon 1 of 9	NP_036370.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT1	ENST00000212015.11	TSL:1 MANE Select	c.76T>G	p.Ser26Ala	missense	Exon 1 of 9	ENSP00000212015.6	Q96EB6-1
	SIRT1	ENST00000923649.1		c.76T>G	p.Ser26Ala	missense	Exon 1 of 10	ENSP00000593708.1
	SIRT1	ENST00000959939.1		c.76T>G	p.Ser26Ala	missense	Exon 1 of 9	ENSP00000629998.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.060
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.39	T
Polyphen		0.064	B
Vest4		0.13
MutPred		0.17		Loss of phosphorylation at S26 (P = 0.0062)
MVP		0.26
MPC		0.25
ClinPred		0.23	T
GERP RS		2.5
PromoterAI		0.0074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.19
Mutation Taster		=92/8	polymorphism

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: rs1202064844; hg19: chr10-69644555;