dbSNP rs1554181180: FARS2:c.613-4A>G (chr6-5404538-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_006567.5(FARS2):c.613-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,422,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FARS2
NM_006567.5 splice_region, intron

Scores

Splicing: ADA: 0.00007367

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.284

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 6-5404538-A-G is Benign according to our data. Variant chr6-5404538-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 473313.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FARS2	NM_006567.5 link	c.613-4A>G		splice_region_variant, intron_variant	Intron 2 of 6	ENST00000274680.9	NP_006558.1	O95363

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FARS2	ENST00000274680.9 link	c.613-4A>G	splice_region_variant, intron_variant	Intron 2 of 6	1	NM_006567.5	ENSP00000274680.4	O95363
FARS2	ENST00000324331.10 link	c.613-4A>G	splice_region_variant, intron_variant	Intron 2 of 6	1		ENSP00000316335.5	O95363
FARS2	ENST00000648580.1 link	n.613-4A>G	splice_region_variant, intron_variant	Intron 2 of 8			ENSP00000497889.1	A0A3B3ITR6
FARS2	ENST00000445533.1 link	c.-4A>G	upstream_gene_variant		3		ENSP00000392525.1	Q5JRF7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1422760

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

704532

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32080

American (AMR)

AF:

0.00

AC:

AN:

40110

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25046

East Asian (EAS)

AF:

0.00

AC:

AN:

39032

South Asian (SAS)

AF:

0.00

AC:

AN:

79018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5266

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1090720

Other (OTH)

AF:

0.00

AC:

AN:

58698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 14

Benign:1

Apr 25, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

9.5

(source)

DANN

Benign

0.81

PhyloP100

0.28

PromoterAI

0.0094

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000074

dbscSNV1_RF

Benign

0.038

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over