6-5368909-C-T

Position:

• chr6-5368909-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006567.5(FARS2):​c.339C>T​(p.Tyr113=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00933 in 1,614,142 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (93 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (148 hom.)
• Consequence: FARS2 NM_006567.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.72

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 6-5368909-C-T is Benign according to our data. Variant chr6-5368909-C-T is described in ClinVar as [Benign]. Clinvar id is 137289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FARS2	NM_006567.5	c.339C>T	p.Tyr113=	synonymous_variant	2/7	ENST00000274680.9	NP_006558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FARS2	ENST00000274680.9	c.339C>T	p.Tyr113=	synonymous_variant	2/7	1	NM_006567.5	ENSP00000274680	P1
FARS2	ENST00000324331.10	c.339C>T	p.Tyr113=	synonymous_variant	2/7	1		ENSP00000316335	P1
FARS2	ENST00000648580.1	c.339C>T	p.Tyr113=	synonymous_variant, NMD_transcript_variant	2/9			ENSP00000497889

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3714 AN: 152140 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00592

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0102 AC: 2565 AN: 251278 Hom.: 55 AF XY: 0.00863 AC XY: 1172 AN XY: 135838

Gnomad AFR exome AF: 0.0717

Gnomad AMR exome AF: 0.00943

Gnomad ASJ exome AF: 0.0278

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00284

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00557

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.00775 AC: 11328 AN: 1461884 Hom.: 148 Cov.: 32 AF XY: 0.00735 AC XY: 5347 AN XY: 727244

Gnomad4 AFR exome AF: 0.0716

Gnomad4 AMR exome AF: 0.00979

Gnomad4 ASJ exome AF: 0.0321

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00290

Gnomad4 FIN exome AF: 0.000861

Gnomad4 NFE exome AF: 0.00586

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0245 AC: 3727 AN: 152258 Hom.: 93 Cov.: 32 AF XY: 0.0239 AC XY: 1777 AN XY: 74434

Gnomad4 AFR AF: 0.0700

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00591

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0155 Hom.: 25

Bravo AF: 0.0283

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00640

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined oxidative phosphorylation defect type 14 Benign:2

Benign, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Jun 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jan 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.47
DANN	Benign	0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs41302853; hg19: chr6-5369142;