19-12924908-T-C

Position:

• chr19-12924908-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004461.3(FARSA):​c.1022A>G​(p.Gln341Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,614,218 control chromosomes in the GnomAD database, including 843 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.021 (65 hom., cov: 32)
  • Exomes 𝑓: 0.030 (778 hom.)
• Consequence: FARSA NM_004461.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.91

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033820271).
• BP6: Variant 19-12924908-T-C is Benign according to our data. Variant chr19-12924908-T-C is described in ClinVar as [Benign]. Clinvar id is 3056814.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0215 (3270/152362) while in subpopulation NFE AF= 0.032 (2179/68030). AF 95% confidence interval is 0.0309. There are 65 homozygotes in gnomad4. There are 1640 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 65 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FARSA	NM_004461.3	c.1022A>G	p.Gln341Arg	missense_variant	9/13	ENST00000314606.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FARSA	ENST00000314606.9	c.1022A>G	p.Gln341Arg	missense_variant	9/13	1	NM_004461.3	P1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3270 AN: 152244 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.00658

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.0220 AC: 5528 AN: 251348 Hom.: 91 AF XY: 0.0217 AC XY: 2952 AN XY: 135874

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.00789

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00222

Gnomad FIN exome AF: 0.0615

Gnomad NFE exome AF: 0.0313

Gnomad OTH exome AF: 0.0243

GnomAD4 exome AF: 0.0301 AC: 43966 AN: 1461856 Hom.: 778 Cov.: 34 AF XY: 0.0294 AC XY: 21354 AN XY: 727228

Gnomad4 AFR exome AF: 0.00520

Gnomad4 AMR exome AF: 0.00789

Gnomad4 ASJ exome AF: 0.00566

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00226

Gnomad4 FIN exome AF: 0.0588

Gnomad4 NFE exome AF: 0.0345

Gnomad4 OTH exome AF: 0.0267

GnomAD4 genome AF: 0.0215 AC: 3270 AN: 152362 Hom.: 65 Cov.: 32 AF XY: 0.0220 AC XY: 1640 AN XY: 74508

Gnomad4 AFR AF: 0.00656

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0577

Gnomad4 NFE AF: 0.0320

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0266 Hom.: 109

Bravo AF: 0.0176

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0322 AC: 124

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0303 AC: 261

ExAC AF: 0.0211 AC: 2564

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0288

EpiControl AF: 0.0270

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

FARSA-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 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	0.098
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.038	T;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.1	.;N;N
REVEL	Benign	0.10
Sift	Benign	0.036	.;D;D
Sift4G	Uncertain	0.053	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.11
MPC		0.43
ClinPred		0.029	T
GERP RS		4.5
Varity_R		0.20
gMVP		0.63

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: rs35087277; hg19: chr19-13035722;