rs113155624

chr6-5368672-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006567.5(FARS2):c.102G>A(p.Ser34=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,614,138 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (121 hom.)
• Consequence: FARS2 NM_006567.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.79

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=-0.91).
• BP6: Variant 6-5368672-G-A is Benign according to our data. Variant chr6-5368672-G-A is described in ClinVar as [Benign]. Clinvar id is 137288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00912 (1389/152252) while in subpopulation SAS AF= 0.0434 (209/4812). AF 95% confidence interval is 0.0386. There are 20 homozygotes in gnomad4. There are 728 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FARS2	NM_006567.5	c.102G>A	p.Ser34=	synonymous_variant	2/7	ENST00000274680.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARS2	ENST00000274680.9	c.102G>A	p.Ser34=	synonymous_variant	2/7	1	NM_006567.5	P1
FARS2	ENST00000324331.10	c.102G>A	p.Ser34=	synonymous_variant	2/7	1		P1
FARS2	ENST00000602691.1	c.102G>A	p.Ser34=	synonymous_variant	3/3	3
FARS2	ENST00000648580.1	c.102G>A	p.Ser34=	synonymous_variant, NMD_transcript_variant	2/9

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1387 AN: 152134 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0436

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00671

GnomAD3 exomes AF: 0.00679 AC: 1703 AN: 250940 Hom.: 43 AF XY: 0.00783 AC XY: 1062 AN XY: 135652

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.0377

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00316 AC: 4613 AN: 1461886 Hom.: 121 Cov.: 32 AF XY: 0.00410 AC XY: 2983 AN XY: 727246

Gnomad4 AFR exome AF: 0.0284

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0366

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000971

Gnomad4 OTH exome AF: 0.00469

GnomAD4 genome AF: 0.00912 AC: 1389 AN: 152252 Hom.: 20 Cov.: 32 AF XY: 0.00978 AC XY: 728 AN XY: 74436

Gnomad4 AFR AF: 0.0266

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0434

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00452 Hom.: 4

Bravo AF: 0.00975

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 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. -

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	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.092
Dann	Benign	0.35

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: rs113155624; hg19: chr6-5368905;