6-5368581-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006567.5(FARS2):c.11C>G(p.Ser4Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FARS2 NM_006567.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.368

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 49 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-5368581-C-G is Pathogenic according to our data. Variant chr6-5368581-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2861363.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FARS2	NM_006567.5	c.11C>G	p.Ser4Ter	stop_gained	2/7	ENST00000274680.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARS2	ENST00000274680.9	c.11C>G	p.Ser4Ter	stop_gained	2/7	1	NM_006567.5	P1
FARS2	ENST00000324331.10	c.11C>G	p.Ser4Ter	stop_gained	2/7	1		P1
FARS2	ENST00000602691.1	c.11C>G	p.Ser4Ter	stop_gained	3/3	3
FARS2	ENST00000648580.1	c.11C>G	p.Ser4Ter	stop_gained, NMD_transcript_variant	2/9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation defect type 14 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 22, 2023

For these reasons, this variant has been classified as Pathogenic. 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 creates a premature translational stop signal (p.Ser4*) in the FARS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FARS2 are known to be pathogenic (PMID: 22833457). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	33
Dann	Benign	0.96
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.024	N
MutationTaster	Benign	1.0	A;A
Vest4		0.23
GERP RS		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-5368814;