2-222656259-A-G

Variant names:

• chr2-222656259-A-G
• rs2044537
• ENST00000938936.1:c.-186T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000938936.1(FARSB):​c.-186T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 578,190 control chromosomes in the GnomAD database, including 198,579 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.85 (56330 hom., cov: 36)
  • Exomes 𝑓: 0.81 (142249 hom.)
• Consequence: FARSB ENST00000938936.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.77
• Publications: 5 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

ENSG00000303347 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000938936.1. 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.-186T>C		upstream_gene	N/A	NP_005678.3
	FARSB	NR_130154.2		n.-167T>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARSB	ENST00000938936.1		c.-186T>C		5_prime_UTR	Exon 1 of 17	ENSP00000608995.1
	FARSB	ENST00000281828.8	TSL:1 MANE Select	c.-186T>C		upstream_gene	N/A	ENSP00000281828.6	Q9NSD9-1
	FARSB	ENST00000875114.1		c.-186T>C		upstream_gene	N/A	ENSP00000545173.1

Frequencies

GnomAD3 genomes AF: 0.853 AC: 129831 AN: 152198 Hom.: 56284 Cov.: 36

Gnomad AFR AF: 0.967

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.850

Gnomad OTH AF: 0.861

GnomAD4 exome AF: 0.809 AC: 344593 AN: 425874 Hom.: 142249 Cov.: 3 AF XY: 0.809 AC XY: 181855 AN XY: 224674

African (AFR) AF: 0.963 AC: 9449 AN: 9808

American (AMR) AF: 0.735 AC: 10118 AN: 13768

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 11755 AN: 13608

East Asian (EAS) AF: 0.408 AC: 10814 AN: 26488

South Asian (SAS) AF: 0.793 AC: 33616 AN: 42398

European-Finnish (FIN) AF: 0.784 AC: 26288 AN: 33538

Middle Eastern (MID) AF: 0.915 AC: 3020 AN: 3302

European-Non Finnish (NFE) AF: 0.849 AC: 219022 AN: 258088

Other (OTH) AF: 0.825 AC: 20511 AN: 24876

GnomAD4 genome AF: 0.853 AC: 129923 AN: 152316 Hom.: 56330 Cov.: 36 AF XY: 0.844 AC XY: 62866 AN XY: 74488

African (AFR) AF: 0.967 AC: 40196 AN: 41588

American (AMR) AF: 0.762 AC: 11659 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 2981 AN: 3470

East Asian (EAS) AF: 0.440 AC: 2278 AN: 5174

South Asian (SAS) AF: 0.777 AC: 3754 AN: 4830

European-Finnish (FIN) AF: 0.786 AC: 8348 AN: 10618

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.850 AC: 57814 AN: 68016

Other (OTH) AF: 0.856 AC: 1812 AN: 2116

Alfa AF: 0.817 Hom.: 3538

Bravo AF: 0.856

Asia WGS AF: 0.640 AC: 2227 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0030
DANN	Benign	0.52
PhyloP100		-2.8
PromoterAI		0.045	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2044537;

hg19: chr2-223520978;

COSMIC: COSV56050190;