rs1553549333

Variant names:

• chr2-222600060-G-TT
• rs1553549333
• NM_005687.5:c.1486delCinsAA

Variant summary

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

The NM_005687.5(FARSB):​c.1486delCinsAA​(p.His496LysfsTer14) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H496R) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FARSB NM_005687.5 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.81
• Publications: 0 publications found

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]

FARSB Gene-Disease associations (from GenCC):

• Rajab interstitial lung disease with brain calcifications 1

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia

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 2-222600060-G-TT is Pathogenic according to our data. Variant chr2-222600060-G-TT is described in ClinVar as Pathogenic. ClinVar VariationId is 487456.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FARSB	NM_005687.5	c.1486delCinsAA	p.His496LysfsTer14	frameshift_variant, missense_variant	Exon 16 of 17	ENST00000281828.8	NP_005678.3
FARSB	XM_006712169.3	c.1189delCinsAA	p.His397LysfsTer14	frameshift_variant, missense_variant	Exon 17 of 18		XP_006712232.1
FARSB	XM_011510466.3	c.1189delCinsAA	p.His397LysfsTer14	frameshift_variant, missense_variant	Exon 17 of 18		XP_011508768.1
FARSB	NR_130154.2	n.1701delCinsAA		non_coding_transcript_exon_variant	Exon 17 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FARSB	ENST00000281828.8	c.1486delCinsAA	p.His496LysfsTer14	frameshift_variant, missense_variant	Exon 16 of 17	1	NM_005687.5	ENSP00000281828.6

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

Sep 08, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

-

Antonellis Laboratory at Michigan, University of Michigan

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: in vitro

- -

not provided Pathogenic:1

Sep 24, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=3/197	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs1553549333; hg19: chr2-223464779;