16-23522873-T-C

Position:

• chr16-23522873-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001083614.2(EARS2):​c.*1498A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 152,284 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EARS2 NM_001083614.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.21

Genes affected

EARS2 (HGNC:29419): (glutamyl-tRNA synthetase 2, mitochondrial) This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of glutamate to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 12 (COXPD12). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

GGA2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-23522873-T-C is Benign according to our data. Variant chr16-23522873-T-C is described in ClinVar as [Benign]. Clinvar id is 318517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0147 (2244/152284) while in subpopulation SAS AF= 0.0199 (96/4828). AF 95% confidence interval is 0.0181. There are 23 homozygotes in gnomad4. There are 1065 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EARS2	NM_001083614.2	c.*1498A>G		3_prime_UTR_variant	9/9	ENST00000449606.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EARS2	ENST00000449606.7	c.*1498A>G		3_prime_UTR_variant	9/9	1	NM_001083614.2	P1
EARS2	ENST00000564987.1	n.2621A>G		non_coding_transcript_exon_variant	9/9	1
EARS2	ENST00000674054.1	c.*1405A>G		3_prime_UTR_variant, NMD_transcript_variant	10/10

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2249 AN: 152166 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0148

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0147 AC: 2244 AN: 152284 Hom.: 23 Cov.: 33 AF XY: 0.0143 AC XY: 1065 AN XY: 74466

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0166 Hom.: 2

Bravo AF: 0.0158

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.85
DANN	Benign	0.21

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: rs113477773; hg19: chr16-23534194;