6-5404683-G-T

Variant names:

• chr6-5404683-G-T
• NM_006567.5:c.754G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006567.5(FARS2):​c.754G>T​(p.Ala252Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FARS2 NM_006567.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.776

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0432913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FARS2	NM_006567.5	c.754G>T	p.Ala252Ser	missense_variant	Exon 3 of 7	ENST00000274680.9	NP_006558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FARS2	ENST00000274680.9	c.754G>T	p.Ala252Ser	missense_variant	Exon 3 of 7	1	NM_006567.5	ENSP00000274680.4
FARS2	ENST00000324331.10	c.754G>T	p.Ala252Ser	missense_variant	Exon 3 of 7	1		ENSP00000316335.5
FARS2	ENST00000445533.1	c.142G>T	p.Ala48Ser	missense_variant	Exon 1 of 3	3		ENSP00000392525.1
FARS2	ENST00000648580.1	n.754G>T		non_coding_transcript_exon_variant	Exon 3 of 9			ENSP00000497889.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445452 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718382

Gnomad4 AFR exome AF: 0.00

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: 0.0000377

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.55
DANN	Benign	0.70
DEOGEN2	Benign	0.037	T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.60	.;T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.055	N;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.30	N;N;N
REVEL	Benign	0.053
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.17
MutPred		0.30		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;
MVP		0.42
MPC		0.14
ClinPred		0.063	T
GERP RS		0.18
Varity_R		0.080
gMVP		0.37

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: chr6-5404916; COSMIC: COSV99213001;