12-120303865-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012240.3(SIRT4):c.304C>T(p.Arg102Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,614,198 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (14 hom., cov: 31)
  • Exomes 𝑓: 0.00066 (12 hom.)
• Consequence: SIRT4 NM_012240.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.55

Genes affected

SIRT4 (HGNC:14932): (sirtuin 4) 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 IV of the sirtuin family. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010032862).
• BP6: Variant 12-120303865-C-T is Benign according to our data. Variant chr12-120303865-C-T is described in ClinVar as [Benign]. Clinvar id is 715657.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00599 (912/152320) while in subpopulation AFR AF= 0.0208 (866/41572). AF 95% confidence interval is 0.0197. There are 14 homozygotes in gnomad4. There are 442 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT4	NM_012240.3	c.304C>T	p.Arg102Cys	missense_variant	2/4	ENST00000202967.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT4	ENST00000202967.4	c.304C>T	p.Arg102Cys	missense_variant	2/4	1	NM_012240.3	P1
SIRT4	ENST00000536460.1	c.127C>T	p.Arg43Cys	missense_variant	2/2	5
SIRT4	ENST00000537892.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 913 AN: 152202 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00161 AC: 405 AN: 251178 Hom.: 7 AF XY: 0.00122 AC XY: 166 AN XY: 135780

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000658 AC: 962 AN: 1461878 Hom.: 12 Cov.: 34 AF XY: 0.000578 AC XY: 420 AN XY: 727244

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00599 AC: 912 AN: 152320 Hom.: 14 Cov.: 31 AF XY: 0.00593 AC XY: 442 AN XY: 74480

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00126 Hom.: 3

Bravo AF: 0.00714

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00201 AC: 244

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-8.0	D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.91
MVP		0.67
MPC		1.1
ClinPred		0.091	T
GERP RS		5.4
Varity_R		0.83
gMVP		0.91

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: rs12307919; hg19: chr12-120741668; COSMIC: COSV104565693; COSMIC: COSV104565693;