6-5368581-C-G

Variant names:

• chr6-5368581-C-G
• NM_006567.5:c.11C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006567.5(FARS2):​c.11C>G​(p.Ser4*) 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 Likely_pathogenic. Variant got 8 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. Fraction of 0.992 CDS is truncated, and there are 2 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 rank	MANE	Protein	UniProt
FARS2	NM_006567.5	c.11C>G	p.Ser4*	stop_gained	Exon 2 of 7	ENST00000274680.9	NP_006558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FARS2	ENST00000274680.9	c.11C>G	p.Ser4*	stop_gained	Exon 2 of 7	1	NM_006567.5	ENSP00000274680.4
FARS2	ENST00000324331.10	c.11C>G	p.Ser4*	stop_gained	Exon 2 of 7	1		ENSP00000316335.5
FARS2	ENST00000602691.1	c.11C>G	p.Ser4*	stop_gained	Exon 3 of 3	3		ENSP00000473394.1
FARS2	ENST00000648580.1	n.11C>G		non_coding_transcript_exon_variant	Exon 2 of 9			ENSP00000497889.1

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

Apr 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. For these reasons, this variant has been classified as Pathogenic. -

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
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;