NM_018127.7:c.2275A>G

Variant names:

• chr17-12993024-T-C
• rs199998904
• NM_018127.7:c.2275A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018127.7(ELAC2):​c.2275A>G​(p.Thr759Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000904 in 1,604,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: ELAC2 NM_018127.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 17

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059909165).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018127.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELAC2	NM_018127.7	MANE Select	c.2275A>G	p.Thr759Ala	missense	Exon 24 of 24	NP_060597.4
	ELAC2	NM_173717.2		c.2272A>G	p.Thr758Ala	missense	Exon 24 of 24	NP_776065.1
	ELAC2	NM_001165962.2		c.2155A>G	p.Thr719Ala	missense	Exon 23 of 23	NP_001159434.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELAC2	ENST00000338034.9	TSL:1 MANE Select	c.2275A>G	p.Thr759Ala	missense	Exon 24 of 24	ENSP00000337445.4
	ELAC2	ENST00000395962.6	TSL:2	c.2218A>G	p.Thr740Ala	missense	Exon 24 of 24	ENSP00000379291.1
	ELAC2	ENST00000426905.7	TSL:2	c.2155A>G	p.Thr719Ala	missense	Exon 23 of 23	ENSP00000405223.3

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151766 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000885

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000368 AC: 9 AN: 244836 AF XY: 0.0000301

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000631

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000937 AC: 136 AN: 1452202 Hom.: 0 Cov.: 32 AF XY: 0.0000775 AC XY: 56 AN XY: 722766

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000224 AC: 1 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000664 AC: 3 AN: 45156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000117 AC: 130 AN: 1110814

Other (OTH) AF: 0.0000332 AC: 2 AN: 60232

GnomAD4 genome AF: 0.0000593 AC: 9 AN: 151884 Hom.: 0 Cov.: 33 AF XY: 0.0000808 AC XY: 6 AN XY: 74250

African (AFR) AF: 0.00 AC: 0 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000284 AC: 3 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000886 AC: 6 AN: 67756

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Combined oxidative phosphorylation defect type 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.16
Sift	Benign	0.44	T
Sift4G	Benign	0.85	T
Polyphen		0.78	P
Vest4		0.031
MVP		0.71
MPC		0.20
ClinPred		0.10	T
GERP RS		4.5
Varity_R		0.055
gMVP		0.29
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs199998904; hg19: chr17-12896341;