NM_006567.5:c.8G>C

Variant names:

• chr6-5368578-G-C
• rs200380429
• NM_006567.5:c.8G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006567.5(FARS2):​c.8G>C​(p.Gly3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,608,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FARS2 NM_006567.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.253
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• hereditary spastic paraplegia 77

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

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03139198).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	NM_006567.5	MANE Select	c.8G>C	p.Gly3Ala	missense	Exon 2 of 7	NP_006558.1	O95363
	FARS2	NM_001318872.2		c.8G>C	p.Gly3Ala	missense	Exon 2 of 7	NP_001305801.1	O95363
	FARS2	NM_001374875.1		c.8G>C	p.Gly3Ala	missense	Exon 2 of 7	NP_001361804.1	O95363

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	ENST00000274680.9	TSL:1 MANE Select	c.8G>C	p.Gly3Ala	missense	Exon 2 of 7	ENSP00000274680.4	O95363
	FARS2	ENST00000324331.10	TSL:1	c.8G>C	p.Gly3Ala	missense	Exon 2 of 7	ENSP00000316335.5	O95363
	FARS2	ENST00000897566.1		c.8G>C	p.Gly3Ala	missense	Exon 3 of 8	ENSP00000567625.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 247112 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456234 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723658

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25676

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108534

Other (OTH) AF: 0.00 AC: 0 AN: 60106

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2106

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.8
DANN	Benign	0.10
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.25
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.054
Sift	Benign	0.79	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.65
MPC		0.17
ClinPred		0.015	T
GERP RS		1.7
Varity_R		0.029
gMVP		0.57
Mutation Taster		=95/5	polymorphism

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: rs200380429; hg19: chr6-5368811;