10-67884783-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_012238.5(SIRT1):​c.62A>C​(p.Asp21Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 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. D21G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05602044).

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>C	p.Asp21Ala	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>C	p.Asp21Ala	missense	Exon 1 of 9	ENSP00000212015.6	Q96EB6-1
	SIRT1	ENST00000923649.1		c.62A>C	p.Asp21Ala	missense	Exon 1 of 10	ENSP00000593708.1
	SIRT1	ENST00000959939.1		c.62A>C	p.Asp21Ala	missense	Exon 1 of 9	ENSP00000629998.1

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 146008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000225

Gnomad SAS AF: 0.000245

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000123 AC: 10 AN: 815976 Hom.: 0 Cov.: 32 AF XY: 0.0000130 AC XY: 5 AN XY: 385412

⚠️ 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: 16770

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9940

East Asian (EAS) AF: 0.0000480 AC: 1 AN: 20844

South Asian (SAS) AF: 0.0000680 AC: 1 AN: 14712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9752

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

European-Non Finnish (NFE) AF: 0.0000114 AC: 8 AN: 704338

Other (OTH) AF: 0.00 AC: 0 AN: 31962

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000137 AC: 2 AN: 146144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71240

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40252

American (AMR) AF: 0.00 AC: 0 AN: 14782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.000225 AC: 1 AN: 4442

South Asian (SAS) AF: 0.000244 AC: 1 AN: 4100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65980

Other (OTH) AF: 0.00 AC: 0 AN: 2068

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.45
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.039
Sift	Benign	0.24	T
Sift4G	Benign	0.39	T
Polyphen		0.018	B
Vest4		0.10
MutPred		0.12		Gain of helix (P = 0.0128)
MVP		0.14
MPC		0.31
ClinPred		0.062	T
GERP RS		3.3
PromoterAI		-0.054	Neutral
Varity_R		0.063
gMVP		0.23
Mutation Taster		=92/8	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;