6-44299434-C-CT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_020745.4(AARS2):c.*1112_*1113insA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 144,334 control chromosomes in the GnomAD database, including 24 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.012 (24 hom., cov: 30)
• Consequence: AARS2 NM_020745.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.43

Genes affected

AARS2 (HGNC:21022): (alanyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. Aminoacyl-tRNA synthetases play critical roles in mRNA translation by charging tRNAs with their cognate amino acids. The encoded protein is a mitochondrial enzyme that specifically aminoacylates alanyl-tRNA. Mutations in this gene are a cause of combined oxidative phosphorylation deficiency 8. [provided by RefSeq, Dec 2011]

POLR1C (HGNC:):

TMEM151B (HGNC:21315): (transmembrane protein 151B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1737/144334) while in subpopulation AFR AF= 0.0345 (1365/39604). AF 95% confidence interval is 0.0329. There are 24 homozygotes in gnomad4. There are 846 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AARS2	NM_020745.4	c.*1112_*1113insA		3_prime_UTR_variant	22/22	ENST00000244571.5
AARS2	XM_005249245.4	c.*1112_*1113insA		3_prime_UTR_variant	20/20
POLR1C	NM_001318876.2	c.946-142442dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARS2	ENST00000244571.5	c.*1112_*1113insA		3_prime_UTR_variant	22/22	1	NM_020745.4	P1
TMEM151B	ENST00000438774.2	c.577-7495dup		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1732 AN: 144306 Hom.: 24 Cov.: 30

Gnomad AFR AF: 0.0344

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00640

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.00101

Gnomad SAS AF: 0.00197

Gnomad FIN AF: 0.00552

Gnomad MID AF: 0.00667

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.00825

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0120 AC: 1737 AN: 144334 Hom.: 24 Cov.: 30 AF XY: 0.0121 AC XY: 846 AN XY: 70200

Gnomad4 AFR AF: 0.0345

Gnomad4 AMR AF: 0.00640

Gnomad4 ASJ AF: 0.000298

Gnomad4 EAS AF: 0.00102

Gnomad4 SAS AF: 0.00220

Gnomad4 FIN AF: 0.00552

Gnomad4 NFE AF: 0.00301

Gnomad4 OTH AF: 0.00821

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs112521684; hg19: chr6-44267171;