6-5368573-G-T

Variant summary

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

The NM_006567.5(FARS2):c.3G>T(p.Met1?) variant causes a start lost 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 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.64

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: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-5368573-G-T is Pathogenic according to our data. Variant chr6-5368573-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1067279.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.3G>T	p.Met1?	start_lost	2/7	ENST00000274680.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARS2	ENST00000274680.9	c.3G>T	p.Met1?	start_lost	2/7	1	NM_006567.5	P1
FARS2	ENST00000324331.10	c.3G>T	p.Met1?	start_lost	2/7	1		P1
FARS2	ENST00000602691.1	c.3G>T	p.Met1?	start_lost	3/3	3
FARS2	ENST00000648580.1	c.3G>T	p.Met1?	start_lost, 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

Jul 14, 2023

This sequence change affects the initiator methionine of the FARS2 mRNA. The next in-frame methionine is located at codon 151. 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. ClinVar contains an entry for this variant (Variation ID: 1067279). This variant disrupts a region of the FARS2 protein in which other variant(s) (p.Tyr144Cys) have been determined to be pathogenic (PMID: 22499341, 22833457, 30177229). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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	-0.060
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.058	T;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.74	N;.;N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0030	B;.;B
Vest4		0.91
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0364);Gain of catalytic residue at M1 (P = 0.0364);Gain of catalytic residue at M1 (P = 0.0364);
MVP		0.77
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.83
gMVP		0.67

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: chr6-5368806;