2-222599911-C-T

Variant names:

• chr2-222599911-C-T
• rs369727146
• NM_005687.5:c.1618+17G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005687.5(FARSB):​c.1618+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000892 in 1,565,790 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (26 hom.)
• Consequence: FARSB NM_005687.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.877
• Publications: 0 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-222599911-C-T is Benign according to our data. Variant chr2-222599911-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1542704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000532 (81/152282) while in subpopulation SAS AF = 0.016 (77/4826). AF 95% confidence interval is 0.0131. There are 1 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 26 AR gene

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.1618+17G>A		intron	N/A	NP_005678.3
	FARSB	NR_130154.2		n.1833+17G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARSB	ENST00000281828.8	TSL:1 MANE Select	c.1618+17G>A		intron	N/A	ENSP00000281828.6	Q9NSD9-1
	FARSB	ENST00000875114.1		c.1732+17G>A		intron	N/A	ENSP00000545173.1
	FARSB	ENST00000875112.1		c.1729+17G>A		intron	N/A	ENSP00000545171.1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00203 AC: 425 AN: 209784 AF XY: 0.00273

Gnomad AFR exome AF: 0.0000690

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000665

Gnomad FIN exome AF: 0.0000491

Gnomad NFE exome AF: 0.0000786

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.000930 AC: 1315 AN: 1413508 Hom.: 26 Cov.: 29 AF XY: 0.00136 AC XY: 953 AN XY: 702458

African (AFR) AF: 0.0000657 AC: 2 AN: 30462

American (AMR) AF: 0.00 AC: 0 AN: 31580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24094

East Asian (EAS) AF: 0.00 AC: 0 AN: 37684

South Asian (SAS) AF: 0.0154 AC: 1204 AN: 78284

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52544

Middle Eastern (MID) AF: 0.00125 AC: 7 AN: 5602

European-Non Finnish (NFE) AF: 0.0000365 AC: 40 AN: 1094980

Other (OTH) AF: 0.00103 AC: 60 AN: 58278

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74460

African (AFR) AF: 0.0000481 AC: 2 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000855 Hom.: 0

Bravo AF: 0.000117

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Rajab interstitial lung disease with brain calcifications 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.60
DANN	Benign	0.46
PhyloP100		-0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs369727146; hg19: chr2-223464630;