chr2-222628884-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_005687.5(FARSB):c.853G>A(p.Glu285Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,456,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FARSB
NM_005687.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.61

Publications

4 publications found

Variant links:

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

FARSB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.802

PP5

Variant 2-222628884-C-T is Pathogenic according to our data. Variant chr2-222628884-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 559418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FARSB	NM_005687.5 link	c.853G>A	p.Glu285Lys	missense_variant	Exon 10 of 17	ENST00000281828.8	NP_005678.3
FARSB	XM_006712169.3 link	c.556G>A	p.Glu186Lys	missense_variant	Exon 11 of 18		XP_006712232.1
FARSB	XM_011510466.3 link	c.556G>A	p.Glu186Lys	missense_variant	Exon 11 of 18		XP_011508768.1
FARSB	NR_130154.2 link	n.1068G>A		non_coding_transcript_exon_variant	Exon 11 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FARSB	ENST00000281828.8 link	c.853G>A	p.Glu285Lys	missense_variant	Exon 10 of 17	1	NM_005687.5	ENSP00000281828.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1456402

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724604

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33352

American (AMR)

AF:

0.00

AC:

AN:

44074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39544

South Asian (SAS)

AF:

0.00

AC:

AN:

85496

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1108658

Other (OTH)

AF:

0.00

AC:

AN:

60176

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0112904), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.395

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

EpiCase

AF:

0.0000550

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rajab interstitial lung disease with brain calcifications

Pathogenic:2

Sep 18, 2024

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jul 15, 2018

Department of Genetics, Sultan Qaboos University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

not provided

Pathogenic:1

Nov 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 285 of the FARSB protein (p.Glu285Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with FARSB-related conditions (PMID: 30014610, 35937029). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 559418). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FARSB protein function. For these reasons, this variant has been classified as Pathogenic.

Rajab interstitial lung disease with brain calcifications 1

Pathogenic:1

Jul 24, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.077

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.56

MutationAssessor

Pathogenic

3.3

PhyloP100

6.6

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.44

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Vest4

0.73

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.82

gMVP

0.91

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over