1-32775843-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_003680.4(YARS1):c.*138G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 808,886 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: YARS1 NM_003680.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.20

Genes affected

YARS1 (HGNC:12840): (tyrosyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Tyrosyl-tRNA synthetase belongs to the class I tRNA synthetase family. Cytokine activities have also been observed for the human tyrosyl-tRNA synthetase, after it is split into two parts, an N-terminal fragment that harbors the catalytic site and a C-terminal fragment found only in the mammalian enzyme. The N-terminal fragment is an interleukin-8-like cytokine, whereas the released C-terminal fragment is an EMAP II-like cytokine. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-32775843-C-T is Benign according to our data. Variant chr1-32775843-C-T is described in ClinVar as [Benign]. Clinvar id is 297146.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00159 (242/152228) while in subpopulation NFE AF= 0.00223 (152/68028). AF 95% confidence interval is 0.00194. There are 0 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YARS1	NM_003680.4	c.*138G>A		3_prime_UTR_variant	13/13	ENST00000373477.9
YARS1	XM_011542347.3	c.*138G>A		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YARS1	ENST00000373477.9	c.*138G>A		3_prime_UTR_variant	13/13	1	NM_003680.4	P1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00187 AC: 1228 AN: 656658 Hom.: 3 Cov.: 9 AF XY: 0.00193 AC XY: 662 AN XY: 342298

Gnomad4 AFR exome AF: 0.000229

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000700

Gnomad4 FIN exome AF: 0.0000246

Gnomad4 NFE exome AF: 0.00184

Gnomad4 OTH exome AF: 0.00294

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74420

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00223

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000953 Hom.: 0

Bravo AF: 0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease dominant intermediate C Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.16
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs41265857; hg19: chr1-33241444;