chr6-5404605-C-T

Position:

• chr6-5404605-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The ENST00000274680.9(FARS2):​c.676C>T​(p.His226Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: FARS2 ENST00000274680.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.35

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011478156).
• BP6: Variant 6-5404605-C-T is Benign according to our data. Variant chr6-5404605-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473314.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FARS2	NM_006567.5	c.676C>T	p.His226Tyr	missense_variant	3/7	ENST00000274680.9	NP_006558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FARS2	ENST00000274680.9	c.676C>T	p.His226Tyr	missense_variant	3/7	1	NM_006567.5	ENSP00000274680	P1
FARS2	ENST00000324331.10	c.676C>T	p.His226Tyr	missense_variant	3/7	1		ENSP00000316335	P1
FARS2	ENST00000445533.1	c.64C>T	p.His22Tyr	missense_variant	1/3	3		ENSP00000392525
FARS2	ENST00000648580.1	c.676C>T	p.His226Tyr	missense_variant, NMD_transcript_variant	3/9			ENSP00000497889

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000423 AC: 106 AN: 250738 Hom.: 0 AF XY: 0.000310 AC XY: 42 AN XY: 135532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.0000808 AC: 118 AN: 1460450 Hom.: 0 Cov.: 31 AF XY: 0.0000716 AC XY: 52 AN XY: 726508

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00260

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: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000183 Hom.: 0

Bravo AF: 0.000234

ExAC AF: 0.000412 AC: 50

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined oxidative phosphorylation defect type 14 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Jun 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	- -

FARS2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.077	T;T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.80	.;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	0.91	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N;N;D
REVEL	Benign	0.041
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.096	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.28
MutPred		0.37		Gain of phosphorylation at H226 (P = 0.0498);Gain of phosphorylation at H226 (P = 0.0498);.;
MVP		0.82
MPC		0.18
ClinPred		0.039	T
GERP RS		2.4
Varity_R		0.20
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

LitVar

Other links and lift over

dbSNP: rs201991648; hg19: chr6-5404838;