chr6-5261059-G-A

Position:

• chr6-5261059-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000324331.10(FARS2):​c.-321G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 692,584 control chromosomes in the GnomAD database, including 30,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (11816 hom., cov: 34)
  • Exomes 𝑓: 0.25 (19159 hom.)
• Consequence: FARS2 ENST00000324331.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.616

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-5261059-G-A is Benign according to our data. Variant chr6-5261059-G-A is described in ClinVar as [Benign]. Clinvar id is 676237.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FARS2	NM_001318872.2	c.-321G>A		5_prime_UTR_variant	1/7
FARS2	NM_001374878.1	c.-354G>A		5_prime_UTR_variant	1/7
FARS2	XM_047418087.1	c.-321G>A		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARS2	ENST00000324331.10	c.-321G>A		5_prime_UTR_variant	1/7	1		P1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54382 AN: 152020 Hom.: 11783 Cov.: 34

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.355

GnomAD4 exome AF: 0.255 AC: 137612 AN: 540446 Hom.: 19159 Cov.: 8 AF XY: 0.253 AC XY: 64858 AN XY: 256446

Gnomad4 AFR exome AF: 0.651

Gnomad4 AMR exome AF: 0.348

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.241

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.268

GnomAD4 genome AF: 0.358 AC: 54472 AN: 152138 Hom.: 11816 Cov.: 34 AF XY: 0.352 AC XY: 26159 AN XY: 74372

Gnomad4 AFR AF: 0.612

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.260

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.352

Alfa AF: 0.201 Hom.: 645

Bravo AF: 0.382

Asia WGS AF: 0.245 AC: 855 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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	-0.87
CADD	Benign	2.6
DANN	Benign	0.96

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: rs13191012; hg19: chr6-5261292;