chr6-44299247-G-A

Position:

• chr6-44299247-G-A

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.*1300C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 115,574 control chromosomes in the GnomAD database, including 2,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.20 (2071 hom., cov: 30)
• Consequence: AARS2 NM_020745.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.296

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=-0.88).
• BP6: Variant 6-44299247-G-A is Benign according to our data. Variant chr6-44299247-G-A is described in ClinVar as [Benign]. Clinvar id is 357033.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AARS2	NM_020745.4	c.*1300C>T		3_prime_UTR_variant	22/22	ENST00000244571.5	NP_065796.2
AARS2	XM_005249245.4	c.*1300C>T		3_prime_UTR_variant	20/20		XP_005249302.1
POLR1C	NM_001318876.2	c.946-142643G>A		intron_variant			NP_001305805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AARS2	ENST00000244571.5	c.*1300C>T		3_prime_UTR_variant	22/22	1	NM_020745.4	ENSP00000244571	P1
TMEM151B	ENST00000438774.2	c.577-7696G>A		intron_variant		3		ENSP00000409337

Frequencies

GnomAD3 genomes AF: 0.196 AC: 22655 AN: 115468 Hom.: 2068 Cov.: 30

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.217

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

GnomAD4 genome AF: 0.196 AC: 22669 AN: 115574 Hom.: 2071 Cov.: 30 AF XY: 0.207 AC XY: 11461 AN XY: 55494

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.199

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.485

Gnomad4 SAS AF: 0.378

Gnomad4 FIN AF: 0.336

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.220

Alfa AF: 0.146 Hom.: 719

Bravo AF: 0.141

Asia WGS AF: 0.297 AC: 1030 AN: 3474

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	-0.88
CADD	Benign	3.3
DANN	Benign	0.64

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: rs1123523; hg19: chr6-44266984;