rs1553549333

Positions:

• chr2-222600059-TG-TTT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000281828.8(FARSB):​c.1486delinsAA​(p.His496LysfsTer14) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FARSB ENST00000281828.8 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.81

Genes affected

FARSB (HGNC:17800): (phenylalanyl-tRNA synthetase subunit beta) This gene encodes a highly conserved enzyme that belongs to the aminoacyl-tRNA synthetase class IIc subfamily. This enzyme comprises the regulatory beta subunits that form a tetramer with two catalytic alpha subunits. In the presence of ATP, this tetramer is responsible for attaching L-phenylalanine to the terminal adenosine of the appropriate tRNA. A pseudogene located on chromosome 10 has been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.16 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-222600060-G-TT is Pathogenic according to our data. Variant chr2-222600060-G-TT is described in ClinVar as [Pathogenic]. Clinvar id is 487456.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FARSB	NM_005687.5	c.1486delinsAA	p.His496LysfsTer14	frameshift_variant	16/17	ENST00000281828.8	NP_005678.3
FARSB	XM_006712169.3	c.1189delinsAA	p.His397LysfsTer14	frameshift_variant	17/18		XP_006712232.1
FARSB	XM_011510466.3	c.1189delinsAA	p.His397LysfsTer14	frameshift_variant	17/18		XP_011508768.1
FARSB	NR_130154.2	n.1701delinsAA		non_coding_transcript_exon_variant	17/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FARSB	ENST00000281828.8	c.1486delinsAA	p.His496LysfsTer14	frameshift_variant	16/17	1	NM_005687.5	ENSP00000281828	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Rajab interstitial lung disease with brain calcifications Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 08, 2020

- -

Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency Pathogenic:1

Likely pathogenic, no assertion criteria provided

in vitro

Antonellis Laboratory at Michigan, University of Michigan

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 24, 2018

The c.1486delCinsAA variant in the FARSB gene has been published in association with FARSB-related disorders (Antonellis et al., 2018). The c.1486delCinsAA variant causes a frameshift starting with codon Histidine 496, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 14 of the new reading frame, denoted p.His496LysfsX14. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1486delCinsAA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1486delCinsAA as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553549333; hg19: chr2-223464779;