12-120312571-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_012240.3(SIRT4):c.613G>A(p.Val205Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00435 in 1,614,178 control chromosomes in the GnomAD database, including 31 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (19 hom.)
• Consequence: SIRT4 NM_012240.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.57

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047763884).
• BP6: Variant 12-120312571-G-A is Benign according to our data. Variant chr12-120312571-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2643396.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT4	NM_012240.3	c.613G>A	p.Val205Ile	missense_variant	3/4	ENST00000202967.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT4	ENST00000202967.4	c.613G>A	p.Val205Ile	missense_variant	3/4	1	NM_012240.3	P1
SIRT4	ENST00000537892.1	n.180-13G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 593 AN: 152172 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00548

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00315 AC: 791 AN: 251456 Hom.: 4 AF XY: 0.00344 AC XY: 467 AN XY: 135904

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00533

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00440 AC: 6435 AN: 1461888 Hom.: 19 Cov.: 34 AF XY: 0.00440 AC XY: 3201 AN XY: 727242

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00176

Gnomad4 FIN exome AF: 0.00432

Gnomad4 NFE exome AF: 0.00523

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00389 AC: 593 AN: 152290 Hom.: 12 Cov.: 32 AF XY: 0.00381 AC XY: 284 AN XY: 74462

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00548

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00435 Hom.: 1

Bravo AF: 0.00403

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00370 AC: 449

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00427

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

SIRT4: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.088
Sift	Benign	0.085	T
Sift4G	Benign	0.10	T
Polyphen		0.090	B
Vest4		0.14
MVP		0.30
MPC		0.26
ClinPred		0.013	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs150394622; hg19: chr12-120750374;