chr6-5545284-G-T

Variant names:

• chr6-5545284-G-T
• rs779793214
• NM_006567.5:c.1009G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006567.5(FARS2):​c.1009G>T​(p.Glu337*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E337E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FARS2 NM_006567.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.30
• Publications: 1 publications found

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]

FARS2 Gene-Disease associations (from GenCC):

• metabolic disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• combined oxidative phosphorylation defect type 14

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 77

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006567.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	NM_006567.5	MANE Select	c.1009G>T	p.Glu337*	stop_gained	Exon 5 of 7	NP_006558.1
	FARS2	NM_001318872.2		c.1009G>T	p.Glu337*	stop_gained	Exon 5 of 7	NP_001305801.1
	FARS2	NM_001374875.1		c.1009G>T	p.Glu337*	stop_gained	Exon 5 of 7	NP_001361804.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	ENST00000274680.9	TSL:1 MANE Select	c.1009G>T	p.Glu337*	stop_gained	Exon 5 of 7	ENSP00000274680.4
	FARS2	ENST00000324331.10	TSL:1	c.1009G>T	p.Glu337*	stop_gained	Exon 5 of 7	ENSP00000316335.5
	FARS2	ENST00000648580.1		n.1009G>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000497889.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		6.3
Vest4		0.31
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs779793214; hg19: chr6-5545517;