10-67884768-C-G

Variant names:

• chr10-67884768-C-G
• rs995901311
• NM_012238.5:c.47C>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.47C>G​(p.Ser16Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000929 in 1,075,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S16S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.695
• 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]

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=0.2567553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT1	NM_012238.5	c.47C>G	p.Ser16Trp	missense_variant	Exon 1 of 9	ENST00000212015.11	NP_036370.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRT1	ENST00000212015.11	c.47C>G	p.Ser16Trp	missense_variant	Exon 1 of 9	1	NM_012238.5	ENSP00000212015.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.29e-7 AC: 1 AN: 1075896 Hom.: 0 Cov.: 31 AF XY: 0.00000197 AC XY: 1 AN XY: 508038

African (AFR) AF: 0.00 AC: 0 AN: 22756

American (AMR) AF: 0.00 AC: 0 AN: 8278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14210

East Asian (EAS) AF: 0.00 AC: 0 AN: 26340

South Asian (SAS) AF: 0.00 AC: 0 AN: 19410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2902

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 917616

Other (OTH) AF: 0.0000231 AC: 1 AN: 43344

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.062
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.69
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.072
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.95	P
Vest4		0.41
MutPred		0.24		Gain of catalytic residue at S16 (P = 0.0039);
MVP		0.31
MPC		0.94
ClinPred		0.64	D
GERP RS		1.8
PromoterAI		-0.029	Neutral
Varity_R		0.17
gMVP		0.30
Mutation Taster		=93/7	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: rs995901311; hg19: chr10-69644526;