6-5288973-G-C

Variant names:

• chr6-5288973-G-C
• rs2326584
• NM_006567.5:c.-22+27313G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006567.5(FARS2):​c.-22+27313G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: FARS2 NM_006567.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0590
• Publications: 4 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• hereditary spastic paraplegia 77

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

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=-0.94).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006567.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	NM_006567.5	MANE Select	c.-22+27313G>C		intron	N/A	NP_006558.1	O95363
	FARS2	NM_001318872.2		c.-22+27615G>C		intron	N/A	NP_001305801.1	O95363
	FARS2	NM_001374875.1		c.-22+26855G>C		intron	N/A	NP_001361804.1	O95363

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	ENST00000274680.9	TSL:1 MANE Select	c.-22+27313G>C		intron	N/A	ENSP00000274680.4	O95363
	FARS2	ENST00000324331.10	TSL:1	c.-22+27615G>C		intron	N/A	ENSP00000316335.5	O95363
	FARS2	ENST00000897566.1		c.-22+16484G>C		intron	N/A	ENSP00000567625.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 5080

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.0
DANN	Benign	0.60
PhyloP100		0.059

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2326584;

hg19: chr6-5289206;