rs325010

Variant names:

• chr6-44300181-A-G
• rs325010
• NM_020745.4:c.*366T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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]

ENSG00000272442 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
AARS2	NM_020745.4	c.*366T>C		3_prime_UTR_variant	Exon 22 of 22	ENST00000244571.5	NP_065796.2
AARS2	XM_005249245.4	c.*366T>C		3_prime_UTR_variant	Exon 20 of 20		XP_005249302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARS2	ENST00000244571.5	c.*366T>C		3_prime_UTR_variant	Exon 22 of 22	1	NM_020745.4	ENSP00000244571.4
ENSG00000272442	ENST00000505802.1	n.313-6762A>G		intron_variant	Intron 1 of 9	2		ENSP00000424257.1
TMEM151B	ENST00000438774.2	c.577-6762A>G		intron_variant	Intron 2 of 2	3		ENSP00000409337.2

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

African (AFR) AF: 0.666 AC: 3386 AN: 5084

American (AMR) AF: 0.947 AC: 6904 AN: 7292

Ashkenazi Jewish (ASJ) AF: 0.924 AC: 3624 AN: 3924

East Asian (EAS) AF: 0.999 AC: 7449 AN: 7456

South Asian (SAS) AF: 0.965 AC: 26114 AN: 27054

European-Finnish (FIN) AF: 0.993 AC: 7263 AN: 7312

Middle Eastern (MID) AF: 0.890 AC: 548 AN: 616

European-Non Finnish (NFE) AF: 0.969 AC: 87860 AN: 90632

Other (OTH) AF: 0.948 AC: 7705 AN: 8124

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

African (AFR) AF: 0.675 AC: 27884 AN: 41312

American (AMR) AF: 0.931 AC: 14204 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 3169 AN: 3456

East Asian (EAS) AF: 0.998 AC: 5158 AN: 5170

South Asian (SAS) AF: 0.961 AC: 4633 AN: 4820

European-Finnish (FIN) AF: 0.994 AC: 10511 AN: 10574

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.968 AC: 65664 AN: 67806

Other (OTH) AF: 0.894 AC: 1882 AN: 2104

Alfa AF: 0.909 Hom.: 8261

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs325010; hg19: chr6-44267918;