chr19-12924824-A-G

Position:

• chr19-12924824-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004461.3(FARSA):​c.1027-17T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,611,644 control chromosomes in the GnomAD database, including 1,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (199 hom., cov: 32)
  • Exomes 𝑓: 0.033 (883 hom.)
• Consequence: FARSA NM_004461.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.656

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-12924824-A-G is Benign according to our data. Variant chr19-12924824-A-G is described in ClinVar as [Benign]. Clinvar id is 1255237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FARSA	NM_004461.3	c.1027-17T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000314606.9	NP_004452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FARSA	ENST00000314606.9	c.1027-17T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004461.3	ENSP00000320309	P1

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6659 AN: 152174 Hom.: 197 Cov.: 32

Gnomad AFR AF: 0.0775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0358

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.0224

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.0393

GnomAD3 exomes AF: 0.0314 AC: 7835 AN: 249690 Hom.: 166 AF XY: 0.0304 AC XY: 4106 AN XY: 134986

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0282

Gnomad EAS exome AF: 0.0159

Gnomad SAS exome AF: 0.0303

Gnomad FIN exome AF: 0.00907

Gnomad NFE exome AF: 0.0343

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0330 AC: 48088 AN: 1459352 Hom.: 883 Cov.: 34 AF XY: 0.0328 AC XY: 23766 AN XY: 725560

Gnomad4 AFR exome AF: 0.0808

Gnomad4 AMR exome AF: 0.0231

Gnomad4 ASJ exome AF: 0.0290

Gnomad4 EAS exome AF: 0.0408

Gnomad4 SAS exome AF: 0.0294

Gnomad4 FIN exome AF: 0.0104

Gnomad4 NFE exome AF: 0.0330

Gnomad4 OTH exome AF: 0.0344

GnomAD4 genome AF: 0.0438 AC: 6676 AN: 152292 Hom.: 199 Cov.: 32 AF XY: 0.0414 AC XY: 3082 AN XY: 74470

Gnomad4 AFR AF: 0.0778

Gnomad4 AMR AF: 0.0358

Gnomad4 ASJ AF: 0.0308

Gnomad4 EAS AF: 0.0221

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.00800

Gnomad4 NFE AF: 0.0349

Gnomad4 OTH AF: 0.0389

Alfa AF: 0.0360 Hom.: 137

Bravo AF: 0.0461

Asia WGS AF: 0.0360 AC: 125 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.6
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs8107173; hg19: chr19-13035638;