Genetic Variant FARS2:p.Ala252Ser (chr6-5404683-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006567.5(FARS2):c.754G>T(p.Ala252Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A252P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FARS2
NM_006567.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0432913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FARS2	NM_006567.5 link	c.754G>T	p.Ala252Ser	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>T	p.Ala252Ser	missense_variant	Exon 3 of 7	1	NM_006567.5	ENSP00000274680.4
FARS2	ENST00000324331.10 link	c.754G>T	p.Ala252Ser	missense_variant	Exon 3 of 7	1		ENSP00000316335.5
FARS2	ENST00000445533.1 link	c.142G>T	p.Ala48Ser	missense_variant	Exon 1 of 3	3		ENSP00000392525.1
FARS2	ENST00000648580.1 link	n.754G>T		non_coding_transcript_exon_variant	Exon 3 of 9			ENSP00000497889.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1445452

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33106

American (AMR)

AF:

0.00

AC:

AN:

43536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25752

East Asian (EAS)

AF:

0.00

AC:

AN:

39408

South Asian (SAS)

AF:

0.00

AC:

AN:

82240

European-Finnish (FIN)

AF:

0.0000377

AC:

AN:

52994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5492

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103336

Other (OTH)

AF:

0.00

AC:

AN:

59588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.55

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.037

T;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.60

.;T;T

M_CAP

Benign

0.0072

MetaRNN

Benign

0.043

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.055

N;N;.

PhyloP100

0.78

PrimateAI

Benign

0.30

PROVEAN

Benign

0.30

N;N;N

REVEL

Benign

0.053

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.17

MutPred

0.30

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;

MVP

0.42

MPC

0.14

ClinPred

0.063

GERP RS

0.18

PromoterAI

-0.048

Neutral

(source)

Varity_R

0.080

gMVP

0.37

Mutation Taster

=91/9

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

Computational scores

Splicing

Publications

Other links and lift over