1-32775697-T-C

Position:

• chr1-32775697-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003680.4(YARS1):​c.*284A>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 0.0013 in 503,422 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (2 hom.)
• Consequence: YARS1 NM_003680.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.881

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=-0.79).
• BP6: Variant 1-32775697-T-C is Benign according to our data. Variant chr1-32775697-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 297145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00326 (496/152260) while in subpopulation AFR AF= 0.0116 (483/41558). AF 95% confidence interval is 0.0108. There are 3 homozygotes in gnomad4. There are 240 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YARS1	NM_003680.4	c.*284A>G		3_prime_UTR_variant	13/13	ENST00000373477.9
YARS1	XM_011542347.3	c.*284A>G		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YARS1	ENST00000373477.9	c.*284A>G		3_prime_UTR_variant	13/13	1	NM_003680.4	P1

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 492 AN: 152142 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000456 AC: 160 AN: 351162 Hom.: 2 Cov.: 0 AF XY: 0.000403 AC XY: 74 AN XY: 183836

Gnomad4 AFR exome AF: 0.0114

Gnomad4 AMR exome AF: 0.000714

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000476

Gnomad4 OTH exome AF: 0.000965

GnomAD4 genome AF: 0.00326 AC: 496 AN: 152260 Hom.: 3 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74448

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00313 Hom.: 0

Bravo AF: 0.00373

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2018

- -

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	-0.79
CADD	Benign	9.6
DANN	Benign	0.68
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: rs150690731; hg19: chr1-33241298;