chr10-67884783-A-G

Variant names:

• chr10-67884783-A-G
• rs2131841542
• NM_012238.5:c.62A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012238.5(SIRT1):​c.62A>G​(p.Asp21Gly) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.446
• 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):

• autoimmune disease

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• monogenic diabetes

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064338684).

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.62A>G	p.Asp21Gly	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.62A>G	p.Asp21Gly	missense	Exon 1 of 9	ENSP00000212015.6	Q96EB6-1
	SIRT1	ENST00000923649.1		c.62A>G	p.Asp21Gly	missense	Exon 1 of 10	ENSP00000593708.1
	SIRT1	ENST00000959939.1		c.62A>G	p.Asp21Gly	missense	Exon 1 of 9	ENSP00000629998.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000123 AC: 1 AN: 816198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 385518

⚠️ 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: 16774

American (AMR) AF: 0.00 AC: 0 AN: 5530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9948

East Asian (EAS) AF: 0.00 AC: 0 AN: 20850

South Asian (SAS) AF: 0.00 AC: 0 AN: 14716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2128

European-Non Finnish (NFE) AF: 0.00000142 AC: 1 AN: 704508

Other (OTH) AF: 0.00 AC: 0 AN: 31978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.45
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.068
Sift	Uncertain	0.026	D
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.15		Gain of helix (P = 0.0199)
MVP		0.12
MPC		0.33
ClinPred		0.081	T
GERP RS		3.3
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
gMVP		0.18
Mutation Taster		=91/9	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: rs2131841542; hg19: chr10-69644541;