6-5431107-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N280T) has been classified 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

Publications

29 publications found

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 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary spastic paraplegia 77
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

FARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 137292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
FARS2	NM_006567.5 link	c.839A>G	p.Asn280Ser	missense_variant	Exon 4 of 7	ENST00000274680.9	NP_006558.1	O95363

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FARS2	ENST00000274680.9 link	c.839A>G	p.Asn280Ser	missense_variant	Exon 4 of 7	1	NM_006567.5	ENSP00000274680.4	O95363
FARS2	ENST00000324331.10 link	c.839A>G	p.Asn280Ser	missense_variant	Exon 4 of 7	1		ENSP00000316335.5	O95363
FARS2	ENST00000445533.1 link	c.227A>G	p.Asn76Ser	missense_variant	Exon 2 of 3	3		ENSP00000392525.1	Q5JRF7
FARS2	ENST00000648580.1 link	n.839A>G		non_coding_transcript_exon_variant	Exon 4 of 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

GnomAD2 exomes

AF:

0.222

AC:

55838

AN:

251320

AF XY:

0.223

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 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

African (AFR)

AF:

0.0695

AC:

2325

AN:

33466

American (AMR)

AF:

0.252

AC:

11250

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.284

AC:

7406

AN:

26120

East Asian (EAS)

AF:

0.391

AC:

15503

AN:

39678

South Asian (SAS)

AF:

0.272

AC:

23452

AN:

86148

European-Finnish (FIN)

AF:

0.158

AC:

8456

AN:

53400

Middle Eastern (MID)

AF:

0.189

AC:

1090

AN:

5764

European-Non Finnish (NFE)

AF:

0.181

AC:

200825

AN:

1111558

Other (OTH)

AF:

0.205

AC:

12364

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

11065

22130

33195

44260

55325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7270

14540

21810

29080

36350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.168

AC:

25559

AN:

152170

Hom.:

2666

Cov.:

AF XY:

0.170

AC XY:

12630

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0760

AC:

3155

AN:

41538

American (AMR)

AF:

0.197

AC:

3018

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.273

AC:

948

AN:

3468

East Asian (EAS)

AF:

0.458

AC:

2365

AN:

5168

South Asian (SAS)

AF:

0.288

AC:

1391

AN:

4822

European-Finnish (FIN)

AF:

0.154

AC:

1631

AN:

10578

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.181

AC:

12319

AN:

67990

Other (OTH)

AF:

0.183

AC:

386

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1041

2081

3122

4162

5203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.184

Hom.:

9275

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

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 13, 2018

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Oct 16, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 77

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

3.4

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

Mutation Taster

=65/35

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over