dbSNP rs6924717: FARS2:c.-22+42958C>T (chr6-5304618-C-T) – 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+42958C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 152,090 control chromosomes in the GnomAD database, including 2,316 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 0.17 ( 2316 hom., cov: 32)

Consequence

FARS2
NM_006567.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00100

Publications

8 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=-0.83).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FARS2	NM_006567.5 link	c.-22+42958C>T		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+42958C>T	intron_variant	Intron 1 of 6	1	NM_006567.5	ENSP00000274680.4	O95363
FARS2	ENST00000324331.10 link	c.-22+43260C>T	intron_variant	Intron 1 of 6	1		ENSP00000316335.5	O95363
FARS2	ENST00000602691.1 link	c.-22+32129C>T	intron_variant	Intron 2 of 2	3		ENSP00000473394.1	R4GMX6
FARS2	ENST00000648580.1 link	n.-22+42958C>T	intron_variant	Intron 1 of 8			ENSP00000497889.1	A0A3B3ITR6

Frequencies

GnomAD3 genomes

AF:

0.166

AC:

25286

AN:

151972

Hom.:

2313

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.143

Gnomad AMR

AF:

0.120

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.100

Gnomad SAS

AF:

0.192

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.145

Gnomad OTH

AF:

0.153

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

GnomAD4 genome

AF:

0.166

AC:

25308

AN:

152090

Hom.:

2316

Cov.:

AF XY:

0.163

AC XY:

12085

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.238

AC:

9865

AN:

41456

American (AMR)

AF:

0.120

AC:

1840

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

695

AN:

3470

East Asian (EAS)

AF:

0.101

AC:

520

AN:

5170

South Asian (SAS)

AF:

0.190

AC:

914

AN:

4810

European-Finnish (FIN)

AF:

0.106

AC:

1119

AN:

10590

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.145

AC:

9854

AN:

67982

Other (OTH)

AF:

0.151

AC:

319

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1068

2137

3205

4274

5342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

278

556

834

1112

1390

<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:

0.155

Hom.:

5847

Bravo

AF:

0.170

Asia WGS

AF:

0.148

AC:

521

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.3

(source)

DANN

Benign

0.87

PhyloP100

-0.0010

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