rs1060502163

Variant names:

• chr17-13016904-A-G
• rs1060502163
• NM_018127.7:c.325T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018127.7(ELAC2):​c.325T>C​(p.Phe109Leu) variant causes a missense change. 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: 31)
• Consequence: ELAC2 NM_018127.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELAC2	NM_018127.7	c.325T>C	p.Phe109Leu	missense_variant	Exon 3 of 24	ENST00000338034.9	NP_060597.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELAC2	ENST00000338034.9	c.325T>C	p.Phe109Leu	missense_variant	Exon 3 of 24	1	NM_018127.7	ENSP00000337445.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation defect type 17 Uncertain:1

Oct 16, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ELAC2-related disease. This sequence change replaces phenylalanine with leucine at codon 109 of the ELAC2 protein (p.Phe109Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;.;.;T;T;T;T;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.5	L;.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.3	D;D;D;.;.;.;.;.;.
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;D;.;.;.;D
Polyphen		1.0	D;D;.;.;.;.;.;.;.
Vest4		0.59
MutPred		0.68		Gain of MoRF binding (P = 0.1233);.;Gain of MoRF binding (P = 0.1233);.;.;.;.;.;Gain of MoRF binding (P = 0.1233);
MVP		0.96
MPC		0.58
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.89
gMVP		0.85

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: rs1060502163; hg19: chr17-12920221;