rs17851782

Positions:

• chr6-5369176-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006567.5(FARS2):​c.606G>A​(p.Lys202=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,605,564 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: FARS2 NM_006567.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.976

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 6-5369176-G-A is Benign according to our data. Variant chr6-5369176-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-5369176-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.976 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FARS2	NM_006567.5	c.606G>A	p.Lys202=	synonymous_variant	2/7	ENST00000274680.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARS2	ENST00000274680.9	c.606G>A	p.Lys202=	synonymous_variant	2/7	1	NM_006567.5	P1
FARS2	ENST00000324331.10	c.606G>A	p.Lys202=	synonymous_variant	2/7	1		P1
FARS2	ENST00000648580.1	c.606G>A	p.Lys202=	synonymous_variant, NMD_transcript_variant	2/9

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152128 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00136 AC: 331 AN: 243370 Hom.: 2 AF XY: 0.00145 AC XY: 191 AN XY: 131994

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00371

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000657

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00180 AC: 2616 AN: 1453318 Hom.: 3 Cov.: 32 AF XY: 0.00178 AC XY: 1288 AN XY: 723268

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00349

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152246 Hom.: 1 Cov.: 31 AF XY: 0.00125 AC XY: 93 AN XY: 74452

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00219 Hom.: 0

Bravo AF: 0.00144

EpiCase AF: 0.00267

EpiControl AF: 0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FARS2: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 16, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.1
DANN	Benign	0.55
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: rs17851782; hg19: chr6-5369409;