rs1554116357

Variant names:

• chr6-5613212-GGT-AACCAGAATGAA
• rs1554116357
• NM_006567.5:c.1109_1111delGGTinsAACCAGAATGAA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006567.5(FARS2):​c.1109_1111delGGTinsAACCAGAATGAA​(p.Trp370_Leu371delinsTerProGluTerMet) variant causes a stop gained, disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FARS2 NM_006567.5 stop_gained, disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.13
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-5613212-GGT-AACCAGAATGAA is Pathogenic according to our data. Variant chr6-5613212-GGT-AACCAGAATGAA is described in ClinVar as Pathogenic. ClinVar VariationId is 540540.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1109_1111delGGTinsAACCAGAATGAA	p.Trp370_Leu371delinsTerProGluTerMet	stop_gained disruptive_inframe_insertion	N/A	NP_006558.1	O95363
	FARS2	NM_001318872.2		c.1109_1111delGGTinsAACCAGAATGAA	p.Trp370_Leu371delinsTerProGluTerMet	stop_gained disruptive_inframe_insertion	N/A	NP_001305801.1	O95363
	FARS2	NM_001374875.1		c.1109_1111delGGTinsAACCAGAATGAA	p.Trp370_Leu371delinsTerProGluTerMet	stop_gained disruptive_inframe_insertion	N/A	NP_001361804.1	O95363

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	ENST00000274680.9	TSL:1 MANE Select	c.1109_1111delGGTinsAACCAGAATGAA	p.Trp370_Leu371delinsTerProGluTerMet	stop_gained disruptive_inframe_insertion	N/A	ENSP00000274680.4	O95363
	FARS2	ENST00000324331.10	TSL:1	c.1109_1111delGGTinsAACCAGAATGAA	p.Trp370_Leu371delinsTerProGluTerMet	stop_gained disruptive_inframe_insertion	N/A	ENSP00000316335.5	O95363
	FARS2	ENST00000897566.1		c.1109_1111delGGTinsAACCAGAATGAA	p.Trp370_Leu371delinsTerProGluTerMet	stop_gained disruptive_inframe_insertion	N/A	ENSP00000567625.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Combined oxidative phosphorylation defect type 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554116357; hg19: chr6-5613445;