6-5368909-C-T

Variant names:

• chr6-5368909-C-T
• rs41302853
• NM_006567.5:c.339C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006567.5(FARS2):​c.339C>T​(p.Tyr113Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00933 in 1,614,142 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (93 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (148 hom.)
• Consequence: FARS2 NM_006567.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.72
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 6-5368909-C-T is Benign according to our data. Variant chr6-5368909-C-T is described in ClinVar as Benign. ClinVar VariationId is 137289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0679 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.339C>T	p.Tyr113Tyr	synonymous	Exon 2 of 7	NP_006558.1
	FARS2	NM_001318872.2		c.339C>T	p.Tyr113Tyr	synonymous	Exon 2 of 7	NP_001305801.1
	FARS2	NM_001374875.1		c.339C>T	p.Tyr113Tyr	synonymous	Exon 2 of 7	NP_001361804.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	ENST00000274680.9	TSL:1 MANE Select	c.339C>T	p.Tyr113Tyr	synonymous	Exon 2 of 7	ENSP00000274680.4
	FARS2	ENST00000324331.10	TSL:1	c.339C>T	p.Tyr113Tyr	synonymous	Exon 2 of 7	ENSP00000316335.5
	FARS2	ENST00000648580.1		n.339C>T		non_coding_transcript_exon	Exon 2 of 9	ENSP00000497889.1

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3714 AN: 152140 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00592

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0102 AC: 2565 AN: 251278 AF XY: 0.00863

Gnomad AFR exome AF: 0.0717

Gnomad AMR exome AF: 0.00943

Gnomad ASJ exome AF: 0.0278

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00557

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.00775 AC: 11328 AN: 1461884 Hom.: 148 Cov.: 32 AF XY: 0.00735 AC XY: 5347 AN XY: 727244

African (AFR) AF: 0.0716 AC: 2398 AN: 33478

American (AMR) AF: 0.00979 AC: 438 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0321 AC: 840 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00290 AC: 250 AN: 86258

European-Finnish (FIN) AF: 0.000861 AC: 46 AN: 53418

Middle Eastern (MID) AF: 0.0196 AC: 113 AN: 5768

European-Non Finnish (NFE) AF: 0.00586 AC: 6519 AN: 1112010

Other (OTH) AF: 0.0120 AC: 724 AN: 60396

GnomAD4 genome AF: 0.0245 AC: 3727 AN: 152258 Hom.: 93 Cov.: 32 AF XY: 0.0239 AC XY: 1777 AN XY: 74434

African (AFR) AF: 0.0700 AC: 2908 AN: 41548

American (AMR) AF: 0.0164 AC: 251 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00591 AC: 402 AN: 68020

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.0153 Hom.: 36

Bravo AF: 0.0283

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00640

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Combined oxidative phosphorylation defect type 14 (2)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.47
DANN	Benign	0.28
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	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: rs41302853; hg19: chr6-5369142;