2-222571888-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005687.5(FARSB):c.1753G>A(p.Val585Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.868 in 1,612,028 control chromosomes in the GnomAD database, including 609,470 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.83 (53017 hom., cov: 28)
  • Exomes 𝑓: 0.87 (556453 hom.)
• Consequence: FARSB NM_005687.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.741

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.7201125E-7).
• BP6: Variant 2-222571888-C-T is Benign according to our data. Variant chr2-222571888-C-T is described in ClinVar as [Benign]. Clinvar id is 1164813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FARSB	NM_005687.5	c.1753G>A	p.Val585Ile	missense_variant	17/17	ENST00000281828.8
FARSB	XM_006712169.3	c.1456G>A	p.Val486Ile	missense_variant	18/18
FARSB	XM_011510466.3	c.1456G>A	p.Val486Ile	missense_variant	18/18
FARSB	NR_130154.2	n.1968G>A		non_coding_transcript_exon_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARSB	ENST00000281828.8	c.1753G>A	p.Val585Ile	missense_variant	17/17	1	NM_005687.5	P1

Frequencies

GnomAD3 genomes AF: 0.830 AC: 125898 AN: 151740 Hom.: 52984 Cov.: 28

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.941

Gnomad EAS AF: 0.970

Gnomad SAS AF: 0.921

Gnomad FIN AF: 0.924

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.875

Gnomad OTH AF: 0.829

GnomAD3 exomes AF: 0.885 AC: 221251 AN: 249936 Hom.: 98453 AF XY: 0.889 AC XY: 120124 AN XY: 135078

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.896

Gnomad ASJ exome AF: 0.948

Gnomad EAS exome AF: 0.973

Gnomad SAS exome AF: 0.919

Gnomad FIN exome AF: 0.923

Gnomad NFE exome AF: 0.876

Gnomad OTH exome AF: 0.884

GnomAD4 exome AF: 0.872 AC: 1273160 AN: 1460170 Hom.: 556453 Cov.: 39 AF XY: 0.874 AC XY: 634961 AN XY: 726436

Gnomad4 AFR exome AF: 0.670

Gnomad4 AMR exome AF: 0.891

Gnomad4 ASJ exome AF: 0.943

Gnomad4 EAS exome AF: 0.974

Gnomad4 SAS exome AF: 0.917

Gnomad4 FIN exome AF: 0.923

Gnomad4 NFE exome AF: 0.866

Gnomad4 OTH exome AF: 0.868

GnomAD4 genome AF: 0.830 AC: 125980 AN: 151858 Hom.: 53017 Cov.: 28 AF XY: 0.835 AC XY: 61993 AN XY: 74226

Gnomad4 AFR AF: 0.675

Gnomad4 AMR AF: 0.873

Gnomad4 ASJ AF: 0.941

Gnomad4 EAS AF: 0.971

Gnomad4 SAS AF: 0.921

Gnomad4 FIN AF: 0.924

Gnomad4 NFE AF: 0.875

Gnomad4 OTH AF: 0.827

Alfa AF: 0.867 Hom.: 134992

Bravo AF: 0.818

TwinsUK AF: 0.865 AC: 3208

ALSPAC AF: 0.856 AC: 3298

ESP6500AA AF: 0.684 AC: 3012

ESP6500EA AF: 0.868 AC: 7469

ExAC AF: 0.881 AC: 107015

Asia WGS AF: 0.898 AC: 3122 AN: 3478

EpiCase AF: 0.880

EpiControl AF: 0.879

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

FARSB-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	12
Dann	Benign	0.67
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	6.7e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.66	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.068
Sift	Benign	1.0	T
Sift4G	Benign	0.97	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.14
ClinPred		0.0032	T
GERP RS		4.3
Varity_R		0.015
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs7185; hg19: chr2-223436607;