rs761488832

Positions:

• chr17-12996643-A-C
• chr17-12996643-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018127.7(ELAC2):​c.1563T>G​(p.Phe521Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: ELAC2 NM_018127.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.219

Genes affected

ELAC2 (HGNC:14198): (elaC ribonuclease Z 2) The protein encoded by this gene has a C-terminal domain with tRNA 3′ processing endoribonuclease activity, which catalyzes the removal of the 3' trailer from precursor tRNAs. The protein also interacts with activated Smad family member 2 (Smad2) and its nuclear partner forkhead box H1 (also known as FAST-1), and reduced expression can suppress transforming growth factor-beta induced growth arrest. Mutations in this gene result in an increased risk of prostate cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ELAC2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.307624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELAC2	NM_018127.7	c.1563T>G	p.Phe521Leu	missense_variant	17/24	ENST00000338034.9	NP_060597.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELAC2	ENST00000338034.9	c.1563T>G	p.Phe521Leu	missense_variant	17/24	1	NM_018127.7	ENSP00000337445.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation defect type 17 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ELAC2 protein function. ClinVar contains an entry for this variant (Variation ID: 572177). This variant has not been reported in the literature in individuals affected with ELAC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 521 of the ELAC2 protein (p.Phe521Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.75	N;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Benign	0.20
Sift	Benign	0.086	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.20	B;B;.
Vest4		0.60
MutPred		0.58		Loss of catalytic residue at C516 (P = 0.1637);.;.;
MVP		0.65
MPC		0.25
ClinPred		0.91	D
GERP RS		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.59

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: rs761488832; hg19: chr17-12899960;