chr1-32780201-C-G

Position:

• chr1-32780201-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_003680.4(YARS1):​c.1218G>C​(p.Leu406=) variant causes a synonymous change. The variant allele was found at a frequency of 0.098 in 1,614,056 control chromosomes in the GnomAD database, including 8,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L406L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (907 hom., cov: 31)
  • Exomes 𝑓: 0.097 (7745 hom.)
• Consequence: YARS1 NM_003680.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.91

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-32780201-C-G is Benign according to our data. Variant chr1-32780201-C-G is described in ClinVar as [Benign]. Clinvar id is 297151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-32780201-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YARS1	NM_003680.4	c.1218G>C	p.Leu406=	synonymous_variant	11/13	ENST00000373477.9
YARS1	XM_011542347.3	c.588G>C	p.Leu196=	synonymous_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YARS1	ENST00000373477.9	c.1218G>C	p.Leu406=	synonymous_variant	11/13	1	NM_003680.4	P1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15744 AN: 152072 Hom.: 905 Cov.: 31

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0592

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0952

GnomAD3 exomes AF: 0.104 AC: 26054 AN: 251392 Hom.: 1860 AF XY: 0.0968 AC XY: 13150 AN XY: 135856

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.0563

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0607

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.0970

Gnomad OTH exome AF: 0.0980

GnomAD4 exome AF: 0.0974 AC: 142393 AN: 1461866 Hom.: 7745 Cov.: 32 AF XY: 0.0959 AC XY: 69737 AN XY: 727232

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.0553

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0610

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.0993

Gnomad4 OTH exome AF: 0.0908

GnomAD4 genome AF: 0.104 AC: 15760 AN: 152190 Hom.: 907 Cov.: 31 AF XY: 0.106 AC XY: 7863 AN XY: 74438

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.0559

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0590

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.0947

Alfa AF: 0.0959 Hom.: 269

Bravo AF: 0.105

Asia WGS AF: 0.0460 AC: 160 AN: 3478

EpiCase AF: 0.0966

EpiControl AF: 0.0875

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease dominant intermediate C Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.7
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs699005; hg19: chr1-33245802;