1-32775688-T-C

Position:

• chr1-32775688-T-C

Variant summary

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

The NM_003680.4(YARS1):​c.*293A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0362 in 453,694 control chromosomes in the GnomAD database, including 404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (187 hom., cov: 32)
  • Exomes 𝑓: 0.032 (217 hom.)
• Consequence: YARS1 NM_003680.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.129

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-32775688-T-C is Benign according to our data. Variant chr1-32775688-T-C is described in ClinVar as [Benign]. Clinvar id is 297144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YARS1	NM_003680.4	c.*293A>G		3_prime_UTR_variant	13/13	ENST00000373477.9	NP_003671.1
YARS1	XM_011542347.3	c.*293A>G		3_prime_UTR_variant	11/11		XP_011540649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YARS1	ENST00000373477.9	c.*293A>G		3_prime_UTR_variant	13/13	1	NM_003680.4	ENSP00000362576	P1

Frequencies

GnomAD3 genomes AF: 0.0451 AC: 6865 AN: 152128 Hom.: 188 Cov.: 32

Gnomad AFR AF: 0.0766

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0366

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0363

Gnomad OTH AF: 0.0446

GnomAD4 exome AF: 0.0317 AC: 9554 AN: 301448 Hom.: 217 Cov.: 0 AF XY: 0.0308 AC XY: 4832 AN XY: 156962

Gnomad4 AFR exome AF: 0.0755

Gnomad4 AMR exome AF: 0.0277

Gnomad4 ASJ exome AF: 0.0733

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00833

Gnomad4 FIN exome AF: 0.0221

Gnomad4 NFE exome AF: 0.0351

Gnomad4 OTH exome AF: 0.0374

GnomAD4 genome AF: 0.0451 AC: 6869 AN: 152246 Hom.: 187 Cov.: 32 AF XY: 0.0423 AC XY: 3148 AN XY: 74440

Gnomad4 AFR AF: 0.0765

Gnomad4 AMR AF: 0.0366

Gnomad4 ASJ AF: 0.0781

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00725

Gnomad4 FIN AF: 0.0206

Gnomad4 NFE AF: 0.0363

Gnomad4 OTH AF: 0.0441

Alfa AF: 0.0402 Hom.: 134

Bravo AF: 0.0474

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.83
CADD	Benign	11
DANN	Benign	0.65

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: rs16866009; hg19: chr1-33241289;