rs5030739

chr17-12996585-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018127.7(ELAC2):c.1621G>A(p.Ala541Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0371 in 1,614,038 control chromosomes in the GnomAD database, including 1,293 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (97 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1196 hom.)
• Consequence: ELAC2 NM_018127.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 3.67

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009242713).
• BP6: Variant 17-12996585-C-T is Benign according to our data. Variant chr17-12996585-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 5056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-12996585-C-T is described in Lovd as [Benign]. Variant chr17-12996585-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0293 (4465/152274) while in subpopulation SAS AF= 0.0429 (207/4828). AF 95% confidence interval is 0.0385. There are 97 homozygotes in gnomad4. There are 2183 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 97 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELAC2	NM_018127.7	c.1621G>A	p.Ala541Thr	missense_variant	17/24	ENST00000338034.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELAC2	ENST00000338034.9	c.1621G>A	p.Ala541Thr	missense_variant	17/24	1	NM_018127.7	P2

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4467 AN: 152156 Hom.: 97 Cov.: 33

Gnomad AFR AF: 0.00603

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0422

Gnomad FIN AF: 0.0437

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0347 AC: 8725 AN: 251120 Hom.: 190 AF XY: 0.0358 AC XY: 4859 AN XY: 135786

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.0506

Gnomad EAS exome AF: 0.00669

Gnomad SAS exome AF: 0.0439

Gnomad FIN exome AF: 0.0439

Gnomad NFE exome AF: 0.0390

Gnomad OTH exome AF: 0.0408

GnomAD4 exome AF: 0.0379 AC: 55441 AN: 1461764 Hom.: 1196 Cov.: 31 AF XY: 0.0383 AC XY: 27818 AN XY: 727196

Gnomad4 AFR exome AF: 0.00588

Gnomad4 AMR exome AF: 0.0293

Gnomad4 ASJ exome AF: 0.0560

Gnomad4 EAS exome AF: 0.00398

Gnomad4 SAS exome AF: 0.0451

Gnomad4 FIN exome AF: 0.0462

Gnomad4 NFE exome AF: 0.0391

Gnomad4 OTH exome AF: 0.0367

GnomAD4 genome AF: 0.0293 AC: 4465 AN: 152274 Hom.: 97 Cov.: 33 AF XY: 0.0293 AC XY: 2183 AN XY: 74454

Gnomad4 AFR AF: 0.00601

Gnomad4 AMR AF: 0.0308

Gnomad4 ASJ AF: 0.0588

Gnomad4 EAS AF: 0.00560

Gnomad4 SAS AF: 0.0429

Gnomad4 FIN AF: 0.0437

Gnomad4 NFE AF: 0.0397

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0369 Hom.: 169

Bravo AF: 0.0275

TwinsUK AF: 0.0434 AC: 161

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.0391 AC: 336

ExAC AF: 0.0343 AC: 4159

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.0389

EpiControl AF: 0.0385

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency - variant associated with prostate cancer. -

Combined oxidative phosphorylation defect type 17 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of autosomal recessive Combined oxidative phosphorylation deficiency 17 (MIM#615440). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Prostate cancer, hereditary, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2002

- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 15, 2016

- -

Prostate cancer, hereditary, 2;C3809526:Combined oxidative phosphorylation defect type 17 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	21
Dann	Benign	0.81
DEOGEN2	Benign	0.051	T;.;.
Eigen	Benign	-0.081
Eigen_PC	Benign	0.0043
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.0092	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.0	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.34	B;B;.
Vest4		0.29
MPC		0.23
ClinPred		0.043	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.55

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: rs5030739; hg19: chr17-12899902; COSMIC: COSV61648260; COSMIC: COSV61648260;