rs148921184

Positions:

chr6-5771341-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The ENST00000274680.9(FARS2):c.1268G>A(p.Arg423Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R423W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

FARS2
ENST00000274680.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 4.65

Variant links:

Genes affected

FARS2 (HGNC:21062): (phenylalanyl-tRNA synthetase 2, mitochondrial) This gene encodes a protein that transfers phenylalanine to its cognate tRNA. This protein localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene can cause combined oxidative phosphorylation deficiency 14 (Alpers encephalopathy). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

FARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in ENST00000274680.9

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FARS2	NM_006567.5 linkuse as main transcript	c.1268G>A	p.Arg423Gln	missense_variant	7/7	ENST00000274680.9	NP_006558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
FARS2	ENST00000274680.9 linkuse as main transcript	c.1268G>A	p.Arg423Gln	missense_variant	7/7	1	NM_006567.5	ENSP00000274680	P1
FARS2	ENST00000324331.10 linkuse as main transcript	c.1268G>A	p.Arg423Gln	missense_variant	7/7	1		ENSP00000316335	P1
FARS2	ENST00000648580.1 linkuse as main transcript	c.1218-50367G>A		intron_variant, NMD_transcript_variant				ENSP00000497889

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

251270

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

156

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000112

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:

0.000130

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000144

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 14

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 423 of the FARS2 protein (p.Arg423Gln). This variant is present in population databases (rs148921184, gnomAD 0.02%). This missense change has been observed in individual(s) with developmental delay, hypotonia, and speech delay (PMID: 28419689). ClinVar contains an entry for this variant (Variation ID: 214337). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FARS2 protein function. Experimental studies have shown that this missense change affects FARS2 function (PMID: 28419689). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Jun 13, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 01, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 28, 2023

Variant summary: FARS2 c.1268G>A (p.Arg423Gln) results in a conservative amino acid change located in the Ferrodoxin-fold anticodon-binding domain (IPR005121) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251270 control chromosomes. c.1268G>A has been reported in the literature in individuals affected with developmental delay and hypotonia (Kartvelishvili_2017). This report does not provide unequivocal conclusions about association of the variant with FARS2-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28419689). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2022

The c.1268G>A (p.R423Q) alteration is located in exon 7 (coding exon 6) of the FARS2 gene. This alteration results from a G to A substitution at nucleotide position 1268, causing the arginine (R) at amino acid position 423 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2019

Reported in an individual with developmental delay and hypotonia in published literature (Kartvelishvili et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R387Q due to alternative nomenclature; This variant is associated with the following publications: (PMID: 28419689) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

D;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

.;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.2

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;D

Vest4

0.63

MVP

0.96

MPC

0.67

ClinPred

0.87

GERP RS

4.8

Varity_R

0.88

gMVP

0.63

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.

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