chr6-5600205-G-A

Variant names:

• chr6-5600205-G-A
• rs9328321
• NM_006567.5:c.1066-12964G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006567.5(FARS2):​c.1066-12964G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 152,106 control chromosomes in the GnomAD database, including 10,905 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (10905 hom., cov: 33)
• Consequence: FARS2 NM_006567.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.756
• Publications: 13 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 77

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

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.599 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.1066-12964G>A		intron	N/A	NP_006558.1
	FARS2	NM_001318872.2		c.1066-12964G>A		intron	N/A	NP_001305801.1
	FARS2	NM_001374875.1		c.1066-12964G>A		intron	N/A	NP_001361804.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	ENST00000274680.9	TSL:1 MANE Select	c.1066-12964G>A		intron	N/A	ENSP00000274680.4
	FARS2	ENST00000324331.10	TSL:1	c.1066-12964G>A		intron	N/A	ENSP00000316335.5
	FARS2	ENST00000897566.1		c.1066-12964G>A		intron	N/A	ENSP00000567625.1

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51467 AN: 151988 Hom.: 10873 Cov.: 33

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.330

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.339 AC: 51547 AN: 152106 Hom.: 10905 Cov.: 33 AF XY: 0.338 AC XY: 25112 AN XY: 74350

African (AFR) AF: 0.606 AC: 25108 AN: 41452

American (AMR) AF: 0.264 AC: 4040 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1021 AN: 3472

East Asian (EAS) AF: 0.163 AC: 844 AN: 5182

South Asian (SAS) AF: 0.260 AC: 1254 AN: 4826

European-Finnish (FIN) AF: 0.258 AC: 2726 AN: 10566

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15661 AN: 67988

Other (OTH) AF: 0.330 AC: 698 AN: 2114

Alfa AF: 0.273 Hom.: 14314

Bravo AF: 0.351

Asia WGS AF: 0.247 AC: 861 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.18
DANN	Benign	0.19
PhyloP100		-0.76
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: rs9328321; hg19: chr6-5600438;