rs1554116357

Variant names:

• chr6-5613212-GGT-AACCAGAATGAA
• rs1554116357
• NM_006567.5:c.1109_1111delGGTinsAACCAGAATGAA

Variant summary

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

The NM_006567.5(FARS2):​c.1109_1111delGGTinsAACCAGAATGAA​(p.Trp370_Leu371delinsTerProGluTerMet) variant causes a stop gained, disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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, disruptive_inframe_insertion
• 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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
FARS2	NM_006567.5	c.1109_1111delGGTinsAACCAGAATGAA	p.Trp370_Leu371delinsTerProGluTerMet	stop_gained, disruptive_inframe_insertion		ENST00000274680.9	NP_006558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FARS2	ENST00000274680.9	c.1109_1111delGGTinsAACCAGAATGAA	p.Trp370_Leu371delinsTerProGluTerMet	stop_gained, disruptive_inframe_insertion		1	NM_006567.5	ENSP00000274680.4
FARS2	ENST00000324331.10	c.1109_1111delGGTinsAACCAGAATGAA	p.Trp370_Leu371delinsTerProGluTerMet	stop_gained, disruptive_inframe_insertion		1		ENSP00000316335.5
FARS2	ENST00000648580.1	n.1109_1111delGGTinsAACCAGAATGAA		non_coding_transcript_exon_variant	Exon 6 of 9			ENSP00000497889.1

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

Sep 28, 2020

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.Trp370*) in the FARS2 gene. It is expected to result in an absent or disrupted protein product. 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 variant has not been reported in the literature in individuals with FARS2-related conditions. 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. Loss-of-function variants in FARS2 are known to be pathogenic (PMID: 22833457). For these reasons, this variant has been classified as Pathogenic. -

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;