rs34382405

Positions:

• chr6-5368740-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006567.5(FARS2):​c.170C>G​(p.Ser57Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,614,106 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (17 hom.)
• Consequence: FARS2 NM_006567.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.39

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069410205).
• BP6: Variant 6-5368740-C-G is Benign according to our data. Variant chr6-5368740-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 214327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00757 (1152/152226) while in subpopulation AFR AF= 0.0256 (1061/41522). AF 95% confidence interval is 0.0243. There are 8 homozygotes in gnomad4. There are 539 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FARS2	NM_006567.5	c.170C>G	p.Ser57Cys	missense_variant	2/7	ENST00000274680.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARS2	ENST00000274680.9	c.170C>G	p.Ser57Cys	missense_variant	2/7	1	NM_006567.5	P1
FARS2	ENST00000324331.10	c.170C>G	p.Ser57Cys	missense_variant	2/7	1		P1
FARS2	ENST00000648580.1	c.170C>G	p.Ser57Cys	missense_variant, NMD_transcript_variant	2/9
FARS2	ENST00000602691.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00757 AC: 1152 AN: 152108 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00212 AC: 532 AN: 250918 Hom.: 5 AF XY: 0.00145 AC XY: 196 AN XY: 135622

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000878 AC: 1284 AN: 1461880 Hom.: 17 Cov.: 32 AF XY: 0.000745 AC XY: 542 AN XY: 727240

Gnomad4 AFR exome AF: 0.0251

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00757 AC: 1152 AN: 152226 Hom.: 8 Cov.: 32 AF XY: 0.00724 AC XY: 539 AN XY: 74418

Gnomad4 AFR AF: 0.0256

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00127 Hom.: 1

Bravo AF: 0.00872

ESP6500AA AF: 0.0213 AC: 94

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00248 AC: 301

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

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

Likely 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	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 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
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	-0.075
Eigen_PC	Benign	0.021
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.84	.;T
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.66	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.081
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		0.53	P;P
Vest4		0.44
MVP		0.65
MPC		0.19
ClinPred		0.028	T
GERP RS		5.5
Varity_R		0.20
gMVP		0.62

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: rs34382405; hg19: chr6-5368973;