chr19-12924918-G-A

Position:

• chr19-12924918-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004461.3(FARSA):​c.1012C>T​(p.Arg338Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,614,246 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: FARSA NM_004461.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B:1
• Conservation: PhyloP100: 2.28

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14953321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FARSA	NM_004461.3	c.1012C>T	p.Arg338Cys	missense_variant	9/13	ENST00000314606.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARSA	ENST00000314606.9	c.1012C>T	p.Arg338Cys	missense_variant	9/13	1	NM_004461.3	P1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152254 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000231 AC: 58 AN: 251424 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135902

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000246 AC: 359 AN: 1461874 Hom.: 1 Cov.: 34 AF XY: 0.000274 AC XY: 199 AN XY: 727232

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000215

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152372 Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74506

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000269 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000436

EpiControl AF: 0.00101

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2024

The c.1012C>T (p.R338C) alteration is located in exon 9 (coding exon 9) of the FARSA gene. This alteration results from a C to T substitution at nucleotide position 1012, causing the arginine (R) at amino acid position 338 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

FARSA-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as likely 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	0.092
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.8	.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.3	.;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0060	.;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.0030	.;.;B
Vest4		0.27
MVP		0.75
MPC		0.53
ClinPred		0.30	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs201276620; hg19: chr19-13035732;