rs35224060

Variant names:

• chr10-67916540-A-C
• rs35224060
• NM_012238.5:c.2191A>C

Your query was ambiguous. Multiple possible variants found:

• chr10-67916540-A-C
• chr10-67916540-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012238.5(SIRT1):​c.2191A>C​(p.Ile731Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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: 0.0000014 (0 hom.)
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034977585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIRT1	NM_012238.5	c.2191A>C	p.Ile731Leu	missense_variant	Exon 9 of 9	ENST00000212015.11	NP_036370.2
SIRT1	NM_001142498.2	c.1306A>C	p.Ile436Leu	missense_variant	Exon 8 of 8		NP_001135970.1
SIRT1	NM_001314049.2	c.1282A>C	p.Ile428Leu	missense_variant	Exon 10 of 10		NP_001300978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIRT1	ENST00000212015.11	c.2191A>C	p.Ile731Leu	missense_variant	Exon 9 of 9	1	NM_012238.5	ENSP00000212015.6
SIRT1	ENST00000403579.1	c.1282A>C	p.Ile428Leu	missense_variant	Exon 6 of 6	1		ENSP00000384063.1
SIRT1	ENST00000432464.5	c.1306A>C	p.Ile436Leu	missense_variant	Exon 8 of 8	5		ENSP00000409208.1
SIRT1	ENST00000406900.5	c.1282A>C	p.Ile428Leu	missense_variant	Exon 7 of 7	2		ENSP00000384508.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251028 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727206

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.023
DANN	Benign	0.82
DEOGEN2	Benign	0.24	T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.55	T;T;.;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.035	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.33	N;N;N;N
REVEL	Benign	0.058
Sift	Benign	0.051	T;T;T;T
Sift4G	Benign	0.71	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.079
MutPred		0.13		Loss of methylation at K734 (P = 0.0518);.;.;.;
MVP		0.48
MPC		0.25
ClinPred		0.025	T
GERP RS		-2.4
Varity_R		0.042
gMVP		0.076

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: rs35224060; hg19: chr10-69676297;