rs587777590

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_020745.4(AARS2):ā€‹c.149T>Gā€‹(p.Phe50Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 34)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

AARS2
NM_020745.4 missense

Scores

14
4
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.04
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]
POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 6-44313175-A-C is Pathogenic according to our data. Variant chr6-44313175-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 143045.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AARS2NM_020745.4 linkuse as main transcriptc.149T>G p.Phe50Cys missense_variant 1/22 ENST00000244571.5 NP_065796.2 Q5JTZ9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AARS2ENST00000244571.5 linkuse as main transcriptc.149T>G p.Phe50Cys missense_variant 1/221 NM_020745.4 ENSP00000244571.4 Q5JTZ9
ENSG00000272442ENST00000505802.1 linkuse as main transcriptn.*449+5533A>C intron_variant 2 ENSP00000424257.1 H0Y9J4

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460620
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
726596
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Leukoencephalopathy, progressive, with ovarian failure Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 10, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.65
D
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.87
D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Pathogenic
4.1
H
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-7.1
D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.92
MutPred
0.93
Loss of stability (P = 0.0631);
MVP
0.96
MPC
1.0
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.98
gMVP
0.86

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

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

Other links and lift over

dbSNP: rs587777590; hg19: chr6-44280912; API