rs2753247

Variant names:

• chr6-5261754-A-T
• rs2753247
• NM_006567.5:c.-22+94A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001374875.1(FARS2):​c.-386A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 152,046 control chromosomes in the GnomAD database, including 11,804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (11800 hom., cov: 32)
  • Exomes 𝑓: 0.28 (4 hom.)
• Consequence: FARS2 NM_001374875.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.464
• Publications: 4 publications found

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]

FARS2 Gene-Disease associations (from GenCC):

• metabolic disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• combined oxidative phosphorylation defect type 14

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary spastic paraplegia 77

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-5261754-A-T is Benign according to our data. Variant chr6-5261754-A-T is described in ClinVar as Benign. ClinVar VariationId is 1248756.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374875.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	NM_006567.5	MANE Select	c.-22+94A>T		intron	N/A	NP_006558.1	O95363
	FARS2	NM_001374875.1		c.-386A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001361804.1	O95363
	FARS2	NM_001374877.1		c.-450A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001361806.1	O95363

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	ENST00000274680.9	TSL:1 MANE Select	c.-22+94A>T		intron	N/A	ENSP00000274680.4	O95363
	FARS2	ENST00000324331.10	TSL:1	c.-22+396A>T		intron	N/A	ENSP00000316335.5	O95363
	FARS2	ENST00000897566.1		c.-450A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000567625.1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54326 AN: 151790 Hom.: 11767 Cov.: 32

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.354

GnomAD4 exome AF: 0.275 AC: 38 AN: 138 Hom.: 4 AF XY: 0.281 AC XY: 32 AN XY: 114

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 4 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.267 AC: 32 AN: 120

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.358 AC: 54416 AN: 151908 Hom.: 11800 Cov.: 32 AF XY: 0.352 AC XY: 26123 AN XY: 74224

African (AFR) AF: 0.613 AC: 25397 AN: 41420

American (AMR) AF: 0.357 AC: 5450 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 880 AN: 3466

East Asian (EAS) AF: 0.259 AC: 1339 AN: 5166

South Asian (SAS) AF: 0.165 AC: 794 AN: 4810

European-Finnish (FIN) AF: 0.218 AC: 2297 AN: 10516

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17271 AN: 67952

Other (OTH) AF: 0.351 AC: 738 AN: 2100

Alfa AF: 0.312 Hom.: 1107

Bravo AF: 0.382

Asia WGS AF: 0.245 AC: 854 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.2
DANN	Benign	0.77
PhyloP100		-0.46
PromoterAI		-0.047	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2753247; hg19: chr6-5261987;