NM_012238.5:c.320T>C

Variant names:

• chr10-67885041-T-C
• rs587776957
• NM_012238.5:c.320T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012238.5(SIRT1):​c.320T>C​(p.Leu107Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.148

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT1	NM_012238.5	c.320T>C	p.Leu107Pro	missense_variant	Exon 1 of 9	ENST00000212015.11	NP_036370.2
SIRT1	NM_001142498.2	c.-572T>C		upstream_gene_variant			NP_001135970.1
SIRT1	NM_001314049.2	c.-963T>C		upstream_gene_variant			NP_001300978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRT1	ENST00000212015.11	c.320T>C	p.Leu107Pro	missense_variant	Exon 1 of 9	1	NM_012238.5	ENSP00000212015.6
SIRT1	ENST00000432464.5	c.-572T>C		upstream_gene_variant		5		ENSP00000409208.1
SIRT1	ENST00000473922.1	n.-143T>C		upstream_gene_variant		4
SIRT1	ENST00000497639.5	n.-140T>C		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1264734 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 619832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Variant of unknown significance Uncertain:1

Mar 05, 2013

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.20	N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.23
Sift	Benign	0.13	T
Sift4G	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.71
MutPred		0.22		Gain of glycosylation at P110 (P = 0.0656);
MVP		0.76
MPC		0.40
ClinPred		0.096	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776957; hg19: chr10-69644799;