chr6-44306384-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020745.4(AARS2):c.1196A>G(p.Asn399Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,614,078 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0099 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 12 hom. )

Consequence

AARS2
NM_020745.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.00

Variant links:

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]

AARS2 links:

ENSG00000272442 (HGNC:):

ENSG00000272442 links:

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

TMEM151B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010842055).

BP6

Variant 6-44306384-T-C is Benign according to our data. Variant chr6-44306384-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 136228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00993 (1512/152208) while in subpopulation AFR AF= 0.0345 (1434/41530). AF 95% confidence interval is 0.033. There are 21 homozygotes in gnomad4. There are 706 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARS2	NM_020745.4 link	c.1196A>G	p.Asn399Ser	missense_variant	Exon 9 of 22	ENST00000244571.5	NP_065796.2	Q5JTZ9
AARS2	XM_005249245.4 link	c.905A>G	p.Asn302Ser	missense_variant	Exon 7 of 20		XP_005249302.1
AARS2	XR_007059282.1 link	n.1220A>G		non_coding_transcript_exon_variant	Exon 9 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AARS2	ENST00000244571.5 link	c.1196A>G	p.Asn399Ser	missense_variant	Exon 9 of 22	1	NM_020745.4	ENSP00000244571.4	Q5JTZ9
ENSG00000272442	ENST00000505802.1 link	n.313-559T>C		intron_variant	Intron 1 of 9	2		ENSP00000424257.1	H0Y9J4
TMEM151B	ENST00000438774.2 link	c.577-559T>C		intron_variant	Intron 2 of 2	3		ENSP00000409337.2	Q8IW70-2

Frequencies

GnomAD3 genomes

AF:

0.00994

AC:

1512

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0346

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00251

AC:

632

AN:

251466

Hom.:

AF XY:

0.00174

AC XY:

237

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0351

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00100

AC:

1468

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000836

AC XY:

608

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0361

Gnomad4 AMR exome

AF:

0.00143

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.00214

GnomAD4 genome

AF:

0.00993

AC:

1512

AN:

152208

Hom.:

Cov.:

AF XY:

0.00949

AC XY:

706

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0345

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00181

Hom.:

Bravo

AF:

0.0111

ESP6500AA

AF:

0.0334

AC:

147

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00314

AC:

381

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

May 23, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Combined oxidative phosphorylation defect type 8

Benign:1

Jan 12, 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

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.060

DANN

Benign

0.60

DEOGEN2

Benign

0.088

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.36

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.73

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.2

REVEL

Benign

0.083

Sift

Benign

0.21

Sift4G

Benign

0.19

Polyphen

0.0010

Vest4

0.068

MVP

0.27

MPC

0.18

ClinPred

0.0062

GERP RS

-7.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.4

Varity_R

0.027

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over