rs587776957

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. L107L) has been classified as Likely benign.

• 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
• Publications: 10 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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

African (AFR) AF: 0.00 AC: 0 AN: 25442

American (AMR) AF: 0.00 AC: 0 AN: 19090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20096

East Asian (EAS) AF: 0.00 AC: 0 AN: 27596

South Asian (SAS) AF: 0.00 AC: 0 AN: 63344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5112

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1008858

Other (OTH) AF: 0.00 AC: 0 AN: 50944

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
PhyloP100		0.15
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
PromoterAI		-0.093	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.33
Mutation Taster		=23/77	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: rs587776957; hg19: chr10-69644799;