rs113433939

chr6-44306384-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N399H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0099 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (12 hom.)
• Consequence: AARS2 NM_020745.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.00

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 -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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AARS2	NM_020745.4	c.1196A>G	p.Asn399Ser	missense_variant	9/22	ENST00000244571.5
AARS2	XM_005249245.4	c.905A>G	p.Asn302Ser	missense_variant	7/20
POLR1C	NM_001318876.2	c.946-135506T>C		intron_variant
AARS2	XR_007059282.1	n.1220A>G		non_coding_transcript_exon_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARS2	ENST00000244571.5	c.1196A>G	p.Asn399Ser	missense_variant	9/22	1	NM_020745.4	P1
TMEM151B	ENST00000438774.2	c.577-559T>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00994 AC: 1512 AN: 152088 Hom.: 21 Cov.: 32

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.: 5 AF XY: 0.00174 AC XY: 237 AN XY: 135902

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.: 12 Cov.: 33 AF XY: 0.000836 AC XY: 608 AN XY: 727236

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.: 21 Cov.: 32 AF XY: 0.00949 AC XY: 706 AN XY: 74428

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.: 9

Bravo AF: 0.0111

ESP6500AA AF: 0.0334 AC: 147

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00314 AC: 381

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 23, 2013

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.060
Dann	Benign	0.60
DEOGEN2	Benign	0.088	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.73	N
MutationTaster	Benign	0.99	N;D
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.083
Sift	Benign	0.21	T
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.068
MVP		0.27
MPC		0.18
ClinPred		0.0062	T
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

Other links and lift over

dbSNP: rs113433939; hg19: chr6-44274121;