12-120312897-A-C

Position:

• chr12-120312897-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012240.3(SIRT4):​c.806A>C​(p.Tyr269Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIRT4 NM_012240.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.25

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT4	NM_012240.3	c.806A>C	p.Tyr269Ser	missense_variant	4/4	ENST00000202967.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT4	ENST00000202967.4	c.806A>C	p.Tyr269Ser	missense_variant	4/4	1	NM_012240.3	P1
SIRT4	ENST00000537892.1	n.360A>C		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

The c.806A>C (p.Y269S) alteration is located in exon 4 (coding exon 3) of the SIRT4 gene. This alteration results from a A to C substitution at nucleotide position 806, causing the tyrosine (Y) at amino acid position 269 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.79
MutPred		0.71		Loss of stability (P = 0.0631);
MVP		0.47
MPC		0.99
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.94
gMVP		0.87

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: rs199965697; hg19: chr12-120750700;