rs746746116

Positions:

• chr6-5545200-G-A
• chr6-5545200-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_006567.5(FARS2):​c.925G>A​(p.Gly309Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FARS2 NM_006567.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.51

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 6-5545200-G-A is Pathogenic according to our data. Variant chr6-5545200-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 587672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FARS2	NM_006567.5	c.925G>A	p.Gly309Ser	missense_variant	5/7	ENST00000274680.9	NP_006558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FARS2	ENST00000274680.9	c.925G>A	p.Gly309Ser	missense_variant	5/7	1	NM_006567.5	ENSP00000274680	P1
FARS2	ENST00000324331.10	c.925G>A	p.Gly309Ser	missense_variant	5/7	1		ENSP00000316335	P1
FARS2	ENST00000648580.1	c.925G>A	p.Gly309Ser	missense_variant, NMD_transcript_variant	5/9			ENSP00000497889

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461500 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727052

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined oxidative phosphorylation defect type 14 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.65). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000587672). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Jun 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 19, 2022	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FARS2 function (PMID: 28419689). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FARS2 protein function. ClinVar contains an entry for this variant (Variation ID: 587672). This variant is also known as Gly273Ser. This missense change has been observed in individuals with FARS2-related conditions (PMID: 28419689, 30177229). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 309 of the FARS2 protein (p.Gly309Ser). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.86		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.89
MPC		0.67
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs746746116; hg19: chr6-5545433;