rs2131841433

Variant names:

• chr10-67884744-C-G
• rs2131841433
• NM_012238.5:c.23C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-67884744-C-G
• chr10-67884744-C-T

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.23C>G​(p.Ala8Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,076,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.264
• 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=0.16579053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT1	NM_012238.5	c.23C>G	p.Ala8Gly	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.23C>G	p.Ala8Gly	missense_variant	Exon 1 of 9	1	NM_012238.5	ENSP00000212015.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1076964 Hom.: 0 Cov.: 31 AF XY: 0.00000197 AC XY: 1 AN XY: 508532

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22794

American (AMR) AF: 0.00 AC: 0 AN: 8336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14250

East Asian (EAS) AF: 0.00 AC: 0 AN: 26402

South Asian (SAS) AF: 0.00 AC: 0 AN: 19432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2920

European-Non Finnish (NFE) AF: 0.00000218 AC: 2 AN: 918310

Other (OTH) AF: 0.00 AC: 0 AN: 43442

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.26
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.091
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.23	T
Polyphen		0.85	P
Vest4		0.081
MutPred		0.16		Loss of helix (P = 0.0626);
MVP		0.28
MPC		0.43
ClinPred		0.44	T
GERP RS		2.0
PromoterAI		0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.096
gMVP		0.16
Mutation Taster		=80/20	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: rs2131841433; hg19: chr10-69644502;