rs142073519

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP3BP4BS1_Supporting

The NM_006567.5(FARS2):c.971A>G(p.Tyr324Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000954 in 1,614,040 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Y324Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

FARS2
NM_006567.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 6.77

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

metabolic disease
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
combined oxidative phosphorylation defect type 14
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary spastic paraplegia 77
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

FARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_006567.5

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.31509367).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000466 (71/152280) while in subpopulation AFR AF = 0.00166 (69/41554). AF 95% confidence interval is 0.00135. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FARS2	NM_006567.5 link	c.971A>G	p.Tyr324Cys	missense_variant	Exon 5 of 7	ENST00000274680.9	NP_006558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FARS2	ENST00000274680.9 link	c.971A>G	p.Tyr324Cys	missense_variant	Exon 5 of 7	1	NM_006567.5	ENSP00000274680.4
FARS2	ENST00000324331.10 link	c.971A>G	p.Tyr324Cys	missense_variant	Exon 5 of 7	1		ENSP00000316335.5
FARS2	ENST00000648580.1 link	n.971A>G		non_coding_transcript_exon_variant	Exon 5 of 9			ENSP00000497889.1

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000163

AC:

AN:

251280

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461760

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111898

Other (OTH)

AF:

0.0000497

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000466

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41554

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.000578

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 14

Uncertain:2

Dec 23, 2021

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 324 of the FARS2 protein (p.Tyr324Cys). This variant is present in population databases (rs142073519, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with FARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 214333). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FARS2 protein function with a positive predictive value of 95%. 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. -

not provided

Pathogenic:1

Jul 07, 2014

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Tyr324Cys (TAC>TGC): c.971 A>G in exon 5 of the FARS2 gene (NM_006567.3). The Y324C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Y324C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (D325Y and I329T) have been reported in association with epilepsy, infantile-onset and mitochondrial encephalopathy, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

.;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.32

T;T

MetaSVM

Uncertain

0.012

MutationAssessor

Pathogenic

3.3

M;M

PhyloP100

6.8

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.90

MVP

0.92

MPC

0.75

ClinPred

0.30

GERP RS

5.3

Varity_R

0.87

gMVP

0.88

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over