chr19-12924794-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_004461.3(FARSA):​c.1040C>T​(p.Pro347Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,606,256 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: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

FARSA
NM_004461.3 missense

Scores

12
5
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.62
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.946
PP5
Variant 19-12924794-G-A is Pathogenic according to our data. Variant chr19-12924794-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3068592.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FARSANM_004461.3 linkc.1040C>T p.Pro347Leu missense_variant Exon 10 of 13 ENST00000314606.9 NP_004452.1 Q9Y285-1Q6IBR2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FARSAENST00000314606.9 linkc.1040C>T p.Pro347Leu missense_variant Exon 10 of 13 1 NM_004461.3 ENSP00000320309.3 Q9Y285-1

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152246
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000810
AC:
20
AN:
246852
Hom.:
0
AF XY:
0.0000749
AC XY:
10
AN XY:
133508
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000164
Gnomad SAS exome
AF:
0.0000333
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000143
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000127
AC:
184
AN:
1453892
Hom.:
0
Cov.:
34
AF XY:
0.000120
AC XY:
87
AN XY:
722092
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000506
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000160
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
AF:
0.000144
AC:
22
AN:
152364
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000154
Hom.:
0
Bravo
AF:
0.000125
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000577
AC:
7

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Rajab interstitial lung disease with brain calcifications 2 Pathogenic:1
Dec 23, 2022
Molecular Genetics, Royal Melbourne Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change in FARSA is predicted to replace proline with leucine at codon 347, p.(Pro347Leu). The proline residue is highly conserved (100 vertebrates, UCSC), and is a residue located at the heterodimer interface in the AA tRNA Ligase II domain (PMID: 35918773). There is a moderate physicochemical difference between proline and leucine. The highest population minor allele frequency in gnomAD v2.1 is 0.02% (21/126,978 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been detected in at least two probands compound heterozygous with a variant of uncertain significance (confirmed in trans) with a systemic disorder that included failure to thrive, hepatic dysfunction and progressive interstitial lung disease, and segregated in two affected family members from a single family (PMID: 35918773, https://n.neurology.org/content/98/18_Supplement/1171). An in vitro assay of heterotetramerisation showed the variant failed to form a heteromer with FARSB indicating that this variant impacts protein function (PMID: 35918773). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS3_Supporting, PM1_Supporting, PM2_Supporting, PM3_Supporting, PP1, PP3. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T;.;D
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Pathogenic
5.3
.;.;H
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-9.4
.;D;D
REVEL
Pathogenic
0.74
Sift
Pathogenic
0.0
.;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
.;.;D
Vest4
0.93
MVP
0.94
MPC
1.2
ClinPred
1.0
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.87
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs139805483; hg19: chr19-13035608; API