6-5431107-A-G

Position:

chr6-5431107-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006567.5(FARS2):c.839A>G(p.Asn280Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,613,374 control chromosomes in the GnomAD database, including 32,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2666 hom., cov: 32)

Exomes 𝑓: 0.19 ( 29389 hom. )

Consequence

FARS2
NM_006567.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.40

Variant links:

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 links:

FARS2 (HGNC:):

FARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024745166).

BP6

Variant 6-5431107-A-G is Benign according to our data. Variant chr6-5431107-A-G is described in ClinVar as [Benign]. Clinvar id is 137292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-5431107-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FARS2	NM_006567.5 linkuse as main transcript	c.839A>G	p.Asn280Ser	missense_variant	4/7	ENST00000274680.9	NP_006558.1	O95363

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FARS2	ENST00000274680.9 linkuse as main transcript	c.839A>G	p.Asn280Ser	missense_variant	4/7	1	NM_006567.5	ENSP00000274680.4	O95363
FARS2	ENST00000324331.10 linkuse as main transcript	c.839A>G	p.Asn280Ser	missense_variant	4/7	1		ENSP00000316335.5	O95363
FARS2	ENST00000445533.1 linkuse as main transcript	c.227A>G	p.Asn76Ser	missense_variant	2/3	3		ENSP00000392525.1	Q5JRF7
FARS2	ENST00000648580.1 linkuse as main transcript	n.839A>G		non_coding_transcript_exon_variant	4/9			ENSP00000497889.1	A0A3B3ITR6

Frequencies

GnomAD3 genomes

AF:

0.168

AC:

25547

AN:

152052

Hom.:

2668

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0759

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.273

Gnomad EAS

AF:

0.458

Gnomad SAS

AF:

0.289

Gnomad FIN

AF:

0.154

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.178

GnomAD3 exomes

AF:

0.222

AC:

55838

AN:

251320

Hom.:

7422

AF XY:

0.223

AC XY:

30252

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.0716

Gnomad AMR exome

AF:

0.261

Gnomad ASJ exome

AF:

0.285

Gnomad EAS exome

AF:

0.477

Gnomad SAS exome

AF:

0.277

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.215

GnomAD4 exome

AF:

0.193

AC:

282671

AN:

1461204

Hom.:

29389

Cov.:

AF XY:

0.196

AC XY:

142128

AN XY:

726890

show subpopulations

Gnomad4 AFR exome

AF:

0.0695

Gnomad4 AMR exome

AF:

0.252

Gnomad4 ASJ exome

AF:

0.284

Gnomad4 EAS exome

AF:

0.391

Gnomad4 SAS exome

AF:

0.272

Gnomad4 FIN exome

AF:

0.158

Gnomad4 NFE exome

AF:

0.181

Gnomad4 OTH exome

AF:

0.205

GnomAD4 genome

AF:

0.168

AC:

25559

AN:

152170

Hom.:

2666

Cov.:

AF XY:

0.170

AC XY:

12630

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0760

Gnomad4 AMR

AF:

0.197

Gnomad4 ASJ

AF:

0.273

Gnomad4 EAS

AF:

0.458

Gnomad4 SAS

AF:

0.288

Gnomad4 FIN

AF:

0.154

Gnomad4 NFE

AF:

0.181

Gnomad4 OTH

AF:

0.183

Alfa

AF:

0.189

Hom.:

6695

Bravo

AF:

0.170

TwinsUK

AF:

0.180

AC:

666

ALSPAC

AF:

0.179

AC:

691

ESP6500AA

AF:

0.0738

AC:

325

ESP6500EA

AF:

0.192

AC:

1654

ExAC

AF:

0.219

AC:

26556

Asia WGS

AF:

0.360

AC:

1253

AN:

3478

EpiCase

AF:

0.185

EpiControl

AF:

0.183

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 14

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Jun 13, 2018	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 28% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 26. Only high quality variants are reported. -

Hereditary spastic paraplegia 77

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided

Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.039

T;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.87

.;D;D

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.4

N;N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.85

N;N;N

REVEL

Benign

0.045

Sift

Benign

0.35

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.054

MPC

0.12

ClinPred

0.0055

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over