6-5368587-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006567.5(FARS2):c.17T>C(p.Leu6Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FARS2 NM_006567.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FARS2	NM_006567.5	c.17T>C	p.Leu6Pro	missense_variant	2/7	ENST00000274680.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARS2	ENST00000274680.9	c.17T>C	p.Leu6Pro	missense_variant	2/7	1	NM_006567.5	P1
FARS2	ENST00000324331.10	c.17T>C	p.Leu6Pro	missense_variant	2/7	1		P1
FARS2	ENST00000602691.1	c.17T>C	p.Leu6Pro	missense_variant	3/3	3
FARS2	ENST00000648580.1	c.17T>C	p.Leu6Pro	missense_variant, NMD_transcript_variant	2/9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation defect type 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 03, 2022

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. 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 not expected to disrupt FARS2 protein function. ClinVar contains an entry for this variant (Variation ID: 950127). This variant has not been reported in the literature in individuals affected with FARS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 6 of the FARS2 protein (p.Leu6Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.073	T;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.34	N
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.6	L;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N;.;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0070	D;.;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.95	P;.;P
Vest4		0.89
MutPred		0.61		Loss of stability (P = 0.0021);Loss of stability (P = 0.0021);Loss of stability (P = 0.0021);
MVP		0.83
MPC		0.70
ClinPred		0.74	D
GERP RS		5.0
Varity_R		0.57
gMVP		0.87

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

Other links and lift over

dbSNP: rs1758826838; hg19: chr6-5368820;