6-5404538-A-G

Position:

• chr6-5404538-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_006567.5(FARS2):​c.613-4A>G variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007367
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.284

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 473313.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FARS2	NM_006567.5	c.613-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000274680.9	NP_006558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FARS2	ENST00000274680.9	c.613-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006567.5	ENSP00000274680	P1
FARS2	ENST00000324331.10	c.613-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000316335	P1
FARS2	ENST00000648580.1	c.613-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant				ENSP00000497889
FARS2	ENST00000445533.1			upstream_gene_variant		3		ENSP00000392525

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1422760 Hom.: 0 Cov.: 30 AF XY: 0.00000284 AC XY: 2 AN XY: 704532

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation defect type 14 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.5
DANN	Benign	0.81

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

LitVar

Other links and lift over

dbSNP: rs1554181180; hg19: chr6-5404771;