Genetic Variant FARS2:c.-22+27313G>A (chr6-5288973-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006567.5(FARS2):c.-22+27313G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.787 in 152,138 control chromosomes in the GnomAD database, including 47,932 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.79 ( 47932 hom., cov: 32)

Consequence

FARS2
NM_006567.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0590

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FARS2	NM_006567.5 link	c.-22+27313G>A		intron_variant	Intron 1 of 6	ENST00000274680.9	NP_006558.1	O95363

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FARS2	ENST00000274680.9 link	c.-22+27313G>A	intron_variant	Intron 1 of 6	1	NM_006567.5	ENSP00000274680.4	O95363
FARS2	ENST00000324331.10 link	c.-22+27615G>A	intron_variant	Intron 1 of 6	1		ENSP00000316335.5	O95363
FARS2	ENST00000602691.1 link	c.-22+16484G>A	intron_variant	Intron 2 of 2	3		ENSP00000473394.1	R4GMX6
FARS2	ENST00000648580.1 link	n.-22+27313G>A	intron_variant	Intron 1 of 8			ENSP00000497889.1	A0A3B3ITR6

Frequencies

GnomAD3 genomes

AF:

0.786

AC:

119561

AN:

152022

Hom.:

47870

Cov.:

show subpopulations

Gnomad AFR

AF:

0.944

Gnomad AMI

AF:

0.713

Gnomad AMR

AF:

0.727

Gnomad ASJ

AF:

0.678

Gnomad EAS

AF:

0.831

Gnomad SAS

AF:

0.808

Gnomad FIN

AF:

0.713

Gnomad MID

AF:

0.731

Gnomad NFE

AF:

0.718

Gnomad OTH

AF:

0.760

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.787

AC:

119676

AN:

152138

Hom.:

47932

Cov.:

AF XY:

0.787

AC XY:

58531

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.944

AC:

39213

AN:

41546

American (AMR)

AF:

0.727

AC:

11111

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.678

AC:

2353

AN:

3468

East Asian (EAS)

AF:

0.830

AC:

4293

AN:

5170

South Asian (SAS)

AF:

0.807

AC:

3879

AN:

4806

European-Finnish (FIN)

AF:

0.713

AC:

7528

AN:

10562

Middle Eastern (MID)

AF:

0.721

AC:

212

AN:

294

European-Non Finnish (NFE)

AF:

0.718

AC:

48829

AN:

67976

Other (OTH)

AF:

0.761

AC:

1609

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1242

2484

3726

4968

6210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

862

1724

2586

3448

4310

<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:

0.752

Hom.:

5080

Bravo

AF:

0.793

Asia WGS

AF:

0.828

AC:

2878

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

2.3

(source)

DANN

Benign

0.36

PhyloP100

0.059

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over