rs1554116357

chr6-5613211-TGGT-TAACCAGAATGAA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_006567.5(FARS2):c.1109_1111delinsAACCAGAATGAA(p.Trp370_Leu371delinsTer) variant causes a stop gained change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FARS2 NM_006567.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.13

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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-5613212-GGT-AACCAGAATGAA is Pathogenic according to our data. Variant chr6-5613212-GGT-AACCAGAATGAA is described in ClinVar as [Pathogenic]. Clinvar id is 540540.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.1109_1111delinsAACCAGAATGAA	p.Trp370_Leu371delinsTer	stop_gained	6/7	ENST00000274680.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARS2	ENST00000274680.9	c.1109_1111delinsAACCAGAATGAA	p.Trp370_Leu371delinsTer	stop_gained	6/7	1	NM_006567.5	P1
FARS2	ENST00000324331.10	c.1109_1111delinsAACCAGAATGAA	p.Trp370_Leu371delinsTer	stop_gained	6/7	1		P1
FARS2	ENST00000648580.1	c.1109_1111delinsAACCAGAATGAA	p.Trp370_Leu371delinsTer	stop_gained, NMD_transcript_variant	6/9

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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

Sep 28, 2020

The frequency data for this variant in the population databases is not available, as this variant may be reported as separate entries in the ExAC database. This sequence change creates a premature translational stop signal (p.Trp370*) in the FARS2 gene. It is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with FARS2-related conditions. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in FARS2 are known to be pathogenic (PMID: 22833457). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554116357; hg19: chr6-5613445;