6-5261227-A-C

Variant names:

• chr6-5261227-A-C
• rs9504368
• ENST00000324331:c.-153A>C

Variant summary

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

The NM_001318872.2(FARS2):​c.-153A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 152,892 control chromosomes in the GnomAD database, including 11,826 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (11804 hom., cov: 33)
  • Exomes 𝑓: 0.23 (22 hom.)
• Consequence: FARS2 NM_001318872.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.859

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=-0.95).
• BP6: Variant 6-5261227-A-C is Benign according to our data. Variant chr6-5261227-A-C is described in ClinVar as [Benign]. Clinvar id is 680634.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 rank	MANE	Protein	UniProt
FARS2	NM_001318872.2	c.-153A>C		5_prime_UTR_variant	Exon 1 of 7		NP_001305801.1
FARS2	NM_001374878.1	c.-186A>C		5_prime_UTR_variant	Exon 1 of 7		NP_001361807.1
FARS2	XM_047418087.1	c.-153A>C		5_prime_UTR_variant	Exon 1 of 5		XP_047274043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FARS2	ENST00000324331	c.-153A>C		5_prime_UTR_variant	Exon 1 of 7	1		ENSP00000316335.5

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54346 AN: 151816 Hom.: 11771 Cov.: 33

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.355

GnomAD4 exome AF: 0.233 AC: 223 AN: 958 Hom.: 22 Cov.: 0 AF XY: 0.233 AC XY: 140 AN XY: 600

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.375

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.231

Gnomad4 OTH exome AF: 0.214

GnomAD4 genome AF: 0.358 AC: 54436 AN: 151934 Hom.: 11804 Cov.: 33 AF XY: 0.352 AC XY: 26160 AN XY: 74276

Gnomad4 AFR AF: 0.613

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.260

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.352

Alfa AF: 0.312 Hom.: 1109

Bravo AF: 0.382

Asia WGS AF: 0.243 AC: 848 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.95
CADD	Benign	6.1
DANN	Benign	0.47

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: rs9504368; hg19: chr6-5261460;