6-5298129-A-G

Variant names:

• chr6-5298129-A-G
• rs17140129
• NM_006567.5:c.-22+36469A>G

Variant summary

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

The NM_006567.5(FARS2):​c.-22+36469A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,200 control chromosomes in the GnomAD database, including 2,006 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 0.15 (2006 hom., cov: 33)
• Consequence: FARS2 NM_006567.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• Publications: 6 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 = 0.213 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	NM_006567.5	MANE Select	c.-22+36469A>G		intron	N/A	NP_006558.1
	FARS2	NM_001318872.2		c.-22+36771A>G		intron	N/A	NP_001305801.1
	FARS2	NM_001374875.1		c.-22+36011A>G		intron	N/A	NP_001361804.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	ENST00000274680.9	TSL:1 MANE Select	c.-22+36469A>G		intron	N/A	ENSP00000274680.4
	FARS2	ENST00000324331.10	TSL:1	c.-22+36771A>G		intron	N/A	ENSP00000316335.5
	FARS2	ENST00000602691.1	TSL:3	c.-22+25640A>G		intron	N/A	ENSP00000473394.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23460 AN: 152082 Hom.: 1999 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.151

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

GnomAD4 genome AF: 0.154 AC: 23499 AN: 152200 Hom.: 2006 Cov.: 33 AF XY: 0.150 AC XY: 11170 AN XY: 74408

African (AFR) AF: 0.216 AC: 8983 AN: 41528

American (AMR) AF: 0.110 AC: 1683 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 624 AN: 3472

East Asian (EAS) AF: 0.101 AC: 523 AN: 5184

South Asian (SAS) AF: 0.133 AC: 639 AN: 4822

European-Finnish (FIN) AF: 0.104 AC: 1099 AN: 10580

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9458 AN: 68010

Other (OTH) AF: 0.148 AC: 313 AN: 2108

Alfa AF: 0.151 Hom.: 716

Bravo AF: 0.157

Asia WGS AF: 0.125 AC: 438 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	0.0050
DANN	Benign	0.66
PhyloP100		-1.3
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: rs17140129; hg19: chr6-5298362;