NM_020745.4:c.1774C>T

Variant names:

• chr6-44304512-G-A
• rs138119149
• NM_020745.4:c.1774C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3 PP5_Very_Strong BP4

The NM_020745.4(AARS2):​c.1774C>T​(p.Arg592Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002768351: "Moderate functional evidence supporting abnormal protein function. Cytochrome c oxidase (COX) activity was severely reduced in heart and skeletal muscles of a deceased patient homozygous for the p.R592W variant. Blue-native electrophoresis of mitochondrial respiratory chain complexes demonstrated severely reduced COX and complex I (CI) in the heart, severe COX deficiency and CI reduction in the brain, and partial complex III deficiency in both tissues (PMID:21549344)."; SCV002230847: structural modeling suggests that this variant severely compromises aminoacylation activity (PMID:25705216,¬†21549344,¬†25058219,¬†22277967).; SCV000741177: Structural analysis predicts that this alteration will reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation (Euro, 2015).".

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: AARS2 NM_020745.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 0.555
• Publications: 31 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: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002768351: "Moderate functional evidence supporting abnormal protein function. Cytochrome c oxidase (COX) activity was severely reduced in heart and skeletal muscles of a deceased patient homozygous for the p.R592W variant. Blue-native electrophoresis of mitochondrial respiratory chain complexes demonstrated severely reduced COX and complex I (CI) in the heart, severe COX deficiency and CI reduction in the brain, and partial complex III deficiency in both tissues (PMID: 21549344)."; SCV002230847: structural modeling suggests that this variant severely compromises aminoacylation activity (PMID: 25705216,¬†21549344,¬†25058219,¬†22277967).; SCV000741177: Structural analysis predicts that this alteration will reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation (Euro, 2015).
• PP5: Variant 6-44304512-G-A is Pathogenic according to our data. Variant chr6-44304512-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33908463). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020745.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AARS2	NM_020745.4	MANE Select	c.1774C>T	p.Arg592Trp	missense	Exon 13 of 22	NP_065796.2	Q5JTZ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AARS2	ENST00000244571.5	TSL:1 MANE Select	c.1774C>T	p.Arg592Trp	missense	Exon 13 of 22	ENSP00000244571.4	Q5JTZ9
	ENSG00000272442	ENST00000505802.1	TSL:2	n.313-2431G>A		intron	N/A	ENSP00000424257.1	H0Y9J4
	AARS2	ENST00000965666.1		c.1762C>T	p.Arg588Trp	missense	Exon 13 of 22	ENSP00000635725.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000211 AC: 53 AN: 250804 AF XY: 0.000236

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000248 AC: 363 AN: 1461864 Hom.: 0 Cov.: 34 AF XY: 0.000256 AC XY: 186 AN XY: 727228

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000290 AC: 322 AN: 1111998

Other (OTH) AF: 0.000182 AC: 11 AN: 60396

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74308

African (AFR) AF: 0.0000483 AC: 2 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000272 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Combined oxidative phosphorylation defect type 8 (6)
4	-	-	not provided (4)
2	-	-	Leukoencephalopathy, progressive, with ovarian failure (2)
1	-	-	AARS2-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Pulmonary hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.56
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.76
MVP		0.74
MPC		0.72
ClinPred		0.21	T
GERP RS		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.44
gMVP		0.47
Mutation Taster		=93/7	disease causing (ClinVar)

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: rs138119149; hg19: chr6-44272249; COSMIC: COSV55118256; COSMIC: COSV55118256;