Genetic Variant FARS2:p.Ala252Pro (chr6-5404683-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006567.5(FARS2):c.754G>C(p.Ala252Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. A252G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FARS2
NM_006567.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.776

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.080322325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FARS2	NM_006567.5 link	c.754G>C	p.Ala252Pro	missense_variant	Exon 3 of 7	ENST00000274680.9	NP_006558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FARS2	ENST00000274680.9 link	c.754G>C	p.Ala252Pro	missense_variant	Exon 3 of 7	1	NM_006567.5	ENSP00000274680.4
FARS2	ENST00000324331.10 link	c.754G>C	p.Ala252Pro	missense_variant	Exon 3 of 7	1		ENSP00000316335.5
FARS2	ENST00000445533.1 link	c.142G>C	p.Ala48Pro	missense_variant	Exon 1 of 3	3		ENSP00000392525.1
FARS2	ENST00000648580.1 link	n.754G>C		non_coding_transcript_exon_variant	Exon 3 of 9			ENSP00000497889.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.754G>C (p.A252P) alteration is located in exon 3 (coding exon 2) of the FARS2 gene. This alteration results from a G to C substitution at nucleotide position 754, causing the alanine (A) at amino acid position 252 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

4.4

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.16

T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.0

.;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.080

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.4

M;M;.

PhyloP100

0.78

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.081

Sift

Benign

0.040

D;D;T

Sift4G

Benign

0.11

T;T;T

Vest4

0.36

ClinPred

0.11

GERP RS

0.18

PromoterAI

0.0020

Neutral

(source)

Varity_R

0.70

gMVP

0.81

Mutation Taster

=88/12

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over