6-5261126-A-G

Position:

• chr6-5261126-A-G

Variant summary

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

The ENST00000324331.10(FARS2):​c.-254A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 195,088 control chromosomes in the GnomAD database, including 17,647 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (15810 hom., cov: 34)
  • Exomes 𝑓: 0.28 (1837 hom.)
• Consequence: FARS2 ENST00000324331.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0770

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=-0.97).
• BP6: Variant 6-5261126-A-G is Benign according to our data. Variant chr6-5261126-A-G is described in ClinVar as [Benign]. Clinvar id is 680626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FARS2	NM_001318872.2	c.-254A>G		5_prime_UTR_variant	1/7		NP_001305801.1
FARS2	NM_001374878.1	c.-287A>G		5_prime_UTR_variant	1/7		NP_001361807.1
FARS2	XM_047418087.1	c.-254A>G		5_prime_UTR_variant	1/5		XP_047274043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FARS2	ENST00000324331.10	c.-254A>G		5_prime_UTR_variant	1/7	1		ENSP00000316335	P1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60395 AN: 152134 Hom.: 15768 Cov.: 34

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.387

GnomAD4 exome AF: 0.284 AC: 12165 AN: 42836 Hom.: 1837 Cov.: 4 AF XY: 0.279 AC XY: 5952 AN XY: 21360

Gnomad4 AFR exome AF: 0.817

Gnomad4 AMR exome AF: 0.348

Gnomad4 ASJ exome AF: 0.310

Gnomad4 EAS exome AF: 0.242

Gnomad4 SAS exome AF: 0.193

Gnomad4 FIN exome AF: 0.241

Gnomad4 NFE exome AF: 0.276

Gnomad4 OTH exome AF: 0.320

GnomAD4 genome AF: 0.397 AC: 60490 AN: 152252 Hom.: 15810 Cov.: 34 AF XY: 0.389 AC XY: 28978 AN XY: 74442

Gnomad4 AFR AF: 0.747

Gnomad4 AMR AF: 0.372

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.260

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.384

Alfa AF: 0.336 Hom.: 1406

Bravo AF: 0.428

Asia WGS AF: 0.257 AC: 896 AN: 3476

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	-0.97
CADD	Benign	5.5
DANN	Benign	0.55

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: rs9784870; hg19: chr6-5261359;