Variant 6-5368977-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006567.5(FARS2):c.407C>T(p.Pro136Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FARS2
NM_006567.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84

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.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FARS2	NM_006567.5 linkuse as main transcript	c.407C>T	p.Pro136Leu	missense_variant	2/7	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.407C>T	p.Pro136Leu	missense_variant	2/7	1	NM_006567.5	ENSP00000274680	P1
FARS2	ENST00000324331.10 linkuse as main transcript	c.407C>T	p.Pro136Leu	missense_variant	2/7	1		ENSP00000316335	P1
FARS2	ENST00000648580.1 linkuse as main transcript	c.407C>T	p.Pro136Leu	missense_variant, NMD_transcript_variant	2/9			ENSP00000497889

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000793

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 23, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 136 of the FARS2 protein (p.Pro136Leu). This variant is not present in population databases (gnomAD no frequency). 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: 1485600). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;D

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Pathogenic

4.8

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Uncertain

0.64

Sift

Benign

0.28

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.95

P;P

Vest4

0.67

MutPred

0.79

Loss of disorder (P = 0.0233);Loss of disorder (P = 0.0233);

MVP

0.95

MPC

0.24

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.63

gMVP

0.79

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