rs325010

chr6-44300181-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020745.4(AARS2):c.*366T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 309,194 control chromosomes in the GnomAD database, including 133,211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.88 (60705 hom., cov: 31)
  • Exomes 𝑓: 0.96 (72506 hom.)
• Consequence: AARS2 NM_020745.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.55

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 6-44300181-A-G is Benign according to our data. Variant chr6-44300181-A-G is described in ClinVar as [Benign]. Clinvar id is 357048.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AARS2	NM_020745.4	c.*366T>C		3_prime_UTR_variant	22/22	ENST00000244571.5
AARS2	XM_005249245.4	c.*366T>C		3_prime_UTR_variant	20/20
POLR1C	NM_001318876.2	c.946-141709A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARS2	ENST00000244571.5	c.*366T>C		3_prime_UTR_variant	22/22	1	NM_020745.4	P1
TMEM151B	ENST00000438774.2	c.577-6762A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.885 AC: 134160 AN: 151582 Hom.: 60668 Cov.: 31

Gnomad AFR AF: 0.675

Gnomad AMI AF: 0.987

Gnomad AMR AF: 0.931

Gnomad ASJ AF: 0.917

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.961

Gnomad FIN AF: 0.994

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.968

Gnomad OTH AF: 0.896

GnomAD4 exome AF: 0.958 AC: 150853 AN: 157494 Hom.: 72506 Cov.: 1 AF XY: 0.960 AC XY: 80652 AN XY: 84034

Gnomad4 AFR exome AF: 0.666

Gnomad4 AMR exome AF: 0.947

Gnomad4 ASJ exome AF: 0.924

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.965

Gnomad4 FIN exome AF: 0.993

Gnomad4 NFE exome AF: 0.969

Gnomad4 OTH exome AF: 0.948

GnomAD4 genome AF: 0.885 AC: 134248 AN: 151700 Hom.: 60705 Cov.: 31 AF XY: 0.887 AC XY: 65794 AN XY: 74170

Gnomad4 AFR AF: 0.675

Gnomad4 AMR AF: 0.931

Gnomad4 ASJ AF: 0.917

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.961

Gnomad4 FIN AF: 0.994

Gnomad4 NFE AF: 0.968

Gnomad4 OTH AF: 0.894

Alfa AF: 0.918 Hom.: 8077

Bravo AF: 0.871

Asia WGS AF: 0.938 AC: 3262 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation defect type 8 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	-1.0
Cadd	Benign	0.97
Dann	Benign	0.17

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: rs325010; hg19: chr6-44267918;