Genetic Variant FARSA:p.Val376Leu (chr19-12924708-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004461.3(FARSA):c.1126G>C(p.Val376Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FARSA
NM_004461.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.65

Publications

2 publications found

Variant links:

Genes affected

FARSA (HGNC:3592): (phenylalanyl-tRNA synthetase subunit alpha) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. This gene encodes a product which is similar to the catalytic subunit of prokaryotic and Saccharomyces cerevisiae phenylalanyl-tRNA synthetases (PheRS). This gene product has been shown to be expressed in a tumor-selective and cell cycle stage- and differentiation-dependent manner, the first member of the tRNA synthetase gene family shown to exhibit this type of regulated expression [provided by RefSeq, Jul 2008]

FARSA Gene-Disease associations (from GenCC):

Rajab interstitial lung disease with brain calcifications 2
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

FARSA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40820795).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004461.3. 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
	FARSA	NM_004461.3	MANE Select	c.1126G>C	p.Val376Leu	missense	Exon 10 of 13	NP_004452.1	Q9Y285-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FARSA	ENST00000314606.9	TSL:1 MANE Select	c.1126G>C	p.Val376Leu	missense	Exon 10 of 13	ENSP00000320309.3	Q9Y285-1
FARSA	ENST00000588025.5	TSL:5	c.1246G>C	p.Val416Leu	missense	Exon 11 of 14	ENSP00000468051.1	K7ER00
FARSA	ENST00000941155.1		c.1060G>C	p.Val354Leu	missense	Exon 10 of 13	ENSP00000611214.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714880

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:

33236

American (AMR)

AF:

0.00

AC:

AN:

43812

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24890

East Asian (EAS)

AF:

0.00

AC:

AN:

39388

South Asian (SAS)

AF:

0.00

AC:

AN:

83902

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1099790

Other (OTH)

AF:

0.00

AC:

AN:

59492

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.033

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.046

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.59

PhyloP100

4.7

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.3

REVEL

Benign

0.23

Sift

Benign

0.29

Sift4G

Benign

0.41

Polyphen

0.079

Vest4

0.50

MutPred

0.48

Gain of sheet (P = 0.0827)

MVP

0.63

MPC

0.50

ClinPred

0.71

GERP RS

5.0

Varity_R

0.50

gMVP

0.68

Mutation Taster

=60/40

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over