10-67884761-T-C

Position:

• chr10-67884761-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_012238.5(SIRT1):​c.40T>C​(p.Ser14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,225,138 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (7 hom.)
• Consequence: SIRT1 NM_012238.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 1.46

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 -6 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity SIR1_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0050804913).
• BS2: High AC in GnomAd4 at 348 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRT1	NM_012238.5	c.40T>C	p.Ser14Pro	missense_variant	1/9	ENST00000212015.11	NP_036370.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIRT1	ENST00000212015.11	c.40T>C	p.Ser14Pro	missense_variant	1/9	1	NM_012238.5	ENSP00000212015	P1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 348 AN: 150770 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000925

Gnomad AMI AF: 0.0684

Gnomad AMR AF: 0.00250

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00230

Gnomad FIN AF: 0.0000962

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00242

GnomAD4 exome AF: 0.00306 AC: 3285 AN: 1074260 Hom.: 7 Cov.: 31 AF XY: 0.00303 AC XY: 1539 AN XY: 507230

Gnomad4 AFR exome AF: 0.000353

Gnomad4 AMR exome AF: 0.00133

Gnomad4 ASJ exome AF: 0.0000708

Gnomad4 EAS exome AF: 0.0000382

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.000144

Gnomad4 NFE exome AF: 0.00338

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.00231 AC: 348 AN: 150878 Hom.: 4 Cov.: 33 AF XY: 0.00205 AC XY: 151 AN XY: 73654

Gnomad4 AFR AF: 0.000922

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00230

Gnomad4 FIN AF: 0.0000962

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.00239

Alfa AF: 0.00221 Hom.: 0

Bravo AF: 0.00266

ExAC AF: 0.000490 AC: 12

Asia WGS AF: 0.000586 AC: 2 AN: 3428

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2023	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 14 of the SIRT1 protein (p.Ser14Pro). This variant is present in population databases (rs201230502, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SIRT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1524941). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

SIRT1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.91	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.048
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.053	T
Polyphen		0.0	B
Vest4		0.26
MVP		0.29
MPC		0.48
ClinPred		0.35	T
GERP RS		-0.62
Varity_R		0.26
gMVP		0.16

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: rs201230502; hg19: chr10-69644519; COSMIC: COSV53016928; COSMIC: COSV53016928;