10-67884732-A-G

Variant names:

• chr10-67884732-A-G
• rs1589064382
• NM_012238.5:c.11A>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.11A>G​(p.Glu4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E4D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1894136).

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.11A>G	p.Glu4Gly	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.11A>G	p.Glu4Gly	missense	Exon 1 of 9	ENSP00000212015.6	Q96EB6-1
	SIRT1	ENST00000923649.1		c.11A>G	p.Glu4Gly	missense	Exon 1 of 10	ENSP00000593708.1
	SIRT1	ENST00000959939.1		c.11A>G	p.Glu4Gly	missense	Exon 1 of 9	ENSP00000629998.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.29e-7 AC: 1 AN: 1076272 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 508196

African (AFR) AF: 0.00 AC: 0 AN: 22742

American (AMR) AF: 0.00 AC: 0 AN: 8308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14222

East Asian (EAS) AF: 0.00 AC: 0 AN: 26372

South Asian (SAS) AF: 0.0000516 AC: 1 AN: 19390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2918

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 917870

Other (OTH) AF: 0.00 AC: 0 AN: 43386

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.021
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.15	T
Polyphen		0.73	P
Vest4		0.21
MutPred		0.14		Gain of loop (P = 0.0166)
MVP		0.27
MPC		0.52
ClinPred		0.77	D
GERP RS		3.9
PromoterAI		-0.088	Neutral
Varity_R		0.21
gMVP		0.26
Mutation Taster		=86/14	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: rs1589064382; hg19: chr10-69644490;