rs41302855

Variant names:

• chr6-5545289-C-T
• rs41302855
• NM_006567.5:c.1014C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 2P and 15B. PM2 BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_006567.5(FARS2):​c.1014C>T​(p.Arg338Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: FARS2 NM_006567.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00300

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 Benign. Variant got -13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 6-5545289-C-T is Benign according to our data. Variant chr6-5545289-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 587662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.003 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000664 (97/1461812) while in subpopulation MID AF= 0.00191 (11/5768). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4_exome. There are 57 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FARS2	NM_006567.5	c.1014C>T	p.Arg338Arg	synonymous_variant	Exon 5 of 7	ENST00000274680.9	NP_006558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FARS2	ENST00000274680.9	c.1014C>T	p.Arg338Arg	synonymous_variant	Exon 5 of 7	1	NM_006567.5	ENSP00000274680.4
FARS2	ENST00000324331.10	c.1014C>T	p.Arg338Arg	synonymous_variant	Exon 5 of 7	1		ENSP00000316335.5
FARS2	ENST00000648580.1	n.1014C>T		non_coding_transcript_exon_variant	Exon 5 of 9			ENSP00000497889.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000115 AC: 29 AN: 251300 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.0000784 AC XY: 57 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74464

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.000110

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined oxidative phosphorylation defect type 14 Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 13, 2018

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FARS2-related disorder Benign:1

May 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	4.7
DANN	Benign	0.60

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

LitVar

Other links and lift over

dbSNP: rs41302855; hg19: chr6-5545522;