chr10-67884809-G-T

Variant names:

• chr10-67884809-G-T
• rs948757989
• NM_012238.5:c.88G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012238.5(SIRT1):​c.88G>T​(p.Gly30Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000977 in 1,023,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. G30R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• 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]

SIRT1 Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28782564).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012238.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT1	NM_012238.5	MANE Select	c.88G>T	p.Gly30Trp	missense	Exon 1 of 9	NP_036370.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT1	ENST00000212015.11	TSL:1 MANE Select	c.88G>T	p.Gly30Trp	missense	Exon 1 of 9	ENSP00000212015.6	Q96EB6-1
	SIRT1	ENST00000923649.1		c.88G>T	p.Gly30Trp	missense	Exon 1 of 10	ENSP00000593708.1
	SIRT1	ENST00000959939.1		c.88G>T	p.Gly30Trp	missense	Exon 1 of 9	ENSP00000629998.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.77e-7 AC: 1 AN: 1023120 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 481398

African (AFR) AF: 0.00 AC: 0 AN: 21096

American (AMR) AF: 0.00 AC: 0 AN: 6590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12088

East Asian (EAS) AF: 0.00 AC: 0 AN: 23544

South Asian (SAS) AF: 0.00 AC: 0 AN: 18860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2590

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 884962

Other (OTH) AF: 0.0000252 AC: 1 AN: 39738

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Benign	0.82
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.086
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		0.98	D
Vest4		0.30
MutPred		0.15		Gain of MoRF binding (P = 0.0314)
MVP		0.27
MPC		0.96
ClinPred		0.58	D
GERP RS		3.1
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.17
Mutation Taster		=88/12	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: rs948757989; hg19: chr10-69644567;