rs1489985293

Variant names:

• chr10-67884798-C-A
• rs1489985293
• NM_012238.5:c.77C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-67884798-C-A
• chr10-67884798-C-T

Variant summary

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

The NM_012238.5(SIRT1):​c.77C>A​(p.Ser26*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000934 in 1,070,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: SIRT1 NM_012238.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.576
• 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 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.77C>A	p.Ser26*	stop_gained	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.77C>A	p.Ser26*	stop_gained	Exon 1 of 9	1	NM_012238.5	ENSP00000212015.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.34e-7 AC: 1 AN: 1070956 Hom.: 0 Cov.: 34 AF XY: 0.00000198 AC XY: 1 AN XY: 505720

⚠️ 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: 22582

American (AMR) AF: 0.00 AC: 0 AN: 8108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14000

East Asian (EAS) AF: 0.00 AC: 0 AN: 26152

South Asian (SAS) AF: 0.0000517 AC: 1 AN: 19344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2872

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 914590

Other (OTH) AF: 0.00 AC: 0 AN: 42998

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	37
DANN	Uncertain	0.98
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		0.58
Vest4		0.45
GERP RS		4.1
PromoterAI		-0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=1/199	disease causing (fs/PTC)

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: rs1489985293; hg19: chr10-69644556;