2-222571888-C-T

Variant names:

• chr2-222571888-C-T
• rs7185
• NM_005687.5:c.1753G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: 0.741
• Publications: 36 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: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005687.5. 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
	FARSB	NM_005687.5	MANE Select	c.1753G>A	p.Val585Ile	missense	Exon 17 of 17	NP_005678.3
	FARSB	NR_130154.2		n.1968G>A		non_coding_transcript_exon	Exon 18 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARSB	ENST00000281828.8	TSL:1 MANE Select	c.1753G>A	p.Val585Ile	missense	Exon 17 of 17	ENSP00000281828.6
	FARSB	ENST00000875114.1		c.1867G>A	p.Val623Ile	missense	Exon 18 of 18	ENSP00000545173.1
	FARSB	ENST00000875112.1		c.1864G>A	p.Val622Ile	missense	Exon 18 of 18	ENSP00000545171.1

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

GnomAD2 exomes AF: 0.885 AC: 221251 AN: 249936 AF XY: 0.889

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 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

African (AFR) AF: 0.670 AC: 22368 AN: 33378

American (AMR) AF: 0.891 AC: 39728 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.943 AC: 24594 AN: 26084

East Asian (EAS) AF: 0.974 AC: 38610 AN: 39634

South Asian (SAS) AF: 0.917 AC: 79029 AN: 86138

European-Finnish (FIN) AF: 0.923 AC: 49270 AN: 53400

Middle Eastern (MID) AF: 0.908 AC: 5206 AN: 5734

European-Non Finnish (NFE) AF: 0.866 AC: 961980 AN: 1110858

Other (OTH) AF: 0.868 AC: 52375 AN: 60344

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

African (AFR) AF: 0.675 AC: 27881 AN: 41334

American (AMR) AF: 0.873 AC: 13318 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.941 AC: 3265 AN: 3468

East Asian (EAS) AF: 0.971 AC: 5006 AN: 5158

South Asian (SAS) AF: 0.921 AC: 4402 AN: 4778

European-Finnish (FIN) AF: 0.924 AC: 9790 AN: 10598

Middle Eastern (MID) AF: 0.884 AC: 258 AN: 292

European-Non Finnish (NFE) AF: 0.875 AC: 59443 AN: 67948

Other (OTH) AF: 0.827 AC: 1746 AN: 2112

Alfa AF: 0.861 Hom.: 266406

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	FARSB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.74
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7185; hg19: chr2-223436607; COSMIC: COSV107272703; COSMIC: COSV107272703;