6-5368753-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006567.5(FARS2):c.183C>T(p.Asp61=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,100 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: FARS2 NM_006567.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.640

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 6-5368753-C-T is Benign according to our data. Variant chr6-5368753-C-T is described in ClinVar as [Benign]. Clinvar id is 260002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.64 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00412 (627/152214) while in subpopulation AFR AF= 0.0117 (486/41536). AF 95% confidence interval is 0.0108. There are 4 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FARS2	NM_006567.5	c.183C>T	p.Asp61=	synonymous_variant	2/7	ENST00000274680.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARS2	ENST00000274680.9	c.183C>T	p.Asp61=	synonymous_variant	2/7	1	NM_006567.5	P1
FARS2	ENST00000324331.10	c.183C>T	p.Asp61=	synonymous_variant	2/7	1		P1
FARS2	ENST00000648580.1	c.183C>T	p.Asp61=	synonymous_variant, NMD_transcript_variant	2/9
FARS2	ENST00000602691.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 624 AN: 152096 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00156 AC: 392 AN: 250956 Hom.: 3 AF XY: 0.00140 AC XY: 190 AN XY: 135660

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00153 AC: 2243 AN: 1461886 Hom.: 3 Cov.: 32 AF XY: 0.00144 AC XY: 1044 AN XY: 727242

Gnomad4 AFR exome AF: 0.0133

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.00412 AC: 627 AN: 152214 Hom.: 4 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74422

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00287 Hom.: 5

Bravo AF: 0.00440

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00136

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	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

FARS2: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	0.97
Dann	Benign	0.44

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: rs73718082; hg19: chr6-5368986;