NM_006567.5:c.-70A>G

Variant names:

• chr6-5261612-A-G
• rs2753246
• NM_006567.5:c.-70A>G

Variant summary

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

The NM_006567.5(FARS2):​c.-70A>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 0.359 in 152,166 control chromosomes in the GnomAD database, including 11,956 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (11952 hom., cov: 33)
  • Exomes 𝑓: 0.30 (4 hom.)
• Consequence: FARS2 NM_006567.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.675
• Publications: 8 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=-0.96).
• BP6: Variant 6-5261612-A-G is Benign according to our data. Variant chr6-5261612-A-G is described in ClinVar as Benign. ClinVar VariationId is 1288931.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006567.5. 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.-70A>G		5_prime_UTR	Exon 1 of 7	NP_006558.1	O95363
	FARS2	NM_001374875.1		c.-528A>G		5_prime_UTR	Exon 1 of 7	NP_001361804.1	O95363
	FARS2	NM_001374876.1		c.-134A>G		5_prime_UTR	Exon 1 of 8	NP_001361805.1	O95363

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	ENST00000274680.9	TSL:1 MANE Select	c.-70A>G		5_prime_UTR	Exon 1 of 7	ENSP00000274680.4	O95363
	FARS2	ENST00000324331.10	TSL:1	c.-22+254A>G		intron	N/A	ENSP00000316335.5	O95363
	FARS2	ENST00000897566.1		c.-592A>G		5_prime_UTR	Exon 1 of 8	ENSP00000567625.1

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54576 AN: 151960 Hom.: 11919 Cov.: 33

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.253

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: 0.357

GnomAD4 exome AF: 0.302 AC: 26 AN: 86 Hom.: 4 Cov.: 0 AF XY: 0.333 AC XY: 24 AN XY: 72

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.350 AC: 7 AN: 20

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.300 AC: 15 AN: 50

Other (OTH) AF: 1.00 AC: 2 AN: 2

GnomAD4 genome AF: 0.359 AC: 54666 AN: 152080 Hom.: 11952 Cov.: 33 AF XY: 0.353 AC XY: 26255 AN XY: 74344

African (AFR) AF: 0.618 AC: 25606 AN: 41460

American (AMR) AF: 0.357 AC: 5455 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 880 AN: 3472

East Asian (EAS) AF: 0.259 AC: 1339 AN: 5170

South Asian (SAS) AF: 0.165 AC: 796 AN: 4824

European-Finnish (FIN) AF: 0.218 AC: 2306 AN: 10564

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

European-Non Finnish (NFE) AF: 0.254 AC: 17286 AN: 67998

Other (OTH) AF: 0.354 AC: 747 AN: 2108

Alfa AF: 0.264 Hom.: 2222

Bravo AF: 0.384

Asia WGS AF: 0.244 AC: 853 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	-0.96
CADD	Benign	5.3
DANN	Benign	0.51
PhyloP100		-0.68
PromoterAI		-0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2753246; hg19: chr6-5261845;