rs699005

Variant names:

• chr1-32780201-C-G
• rs699005
• NM_003680.4:c.1218G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-32780201-C-G
• chr1-32780201-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000373477.9(YARS1):​c.1218G>C​(p.Leu406Leu) 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 ENST00000373477.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.91
• Publications: 14 publications found

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]

YARS1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease dominant intermediate C

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 297151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000373477.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS1	NM_003680.4	MANE Select	c.1218G>C	p.Leu406Leu	synonymous	Exon 11 of 13	NP_003671.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS1	ENST00000373477.9	TSL:1 MANE Select	c.1218G>C	p.Leu406Leu	synonymous	Exon 11 of 13	ENSP00000362576.4
	YARS1	ENST00000675785.2		c.1071G>C	p.Leu357Leu	synonymous	Exon 10 of 12	ENSP00000502019.1
	YARS1	ENST00000469100.5	TSL:2	n.1134G>C		non_coding_transcript_exon	Exon 2 of 4

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

GnomAD2 exomes AF: 0.104 AC: 26054 AN: 251392 AF XY: 0.0968

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 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

African (AFR) AF: 0.103 AC: 3446 AN: 33480

American (AMR) AF: 0.210 AC: 9388 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0553 AC: 1445 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0610 AC: 5258 AN: 86258

European-Finnish (FIN) AF: 0.126 AC: 6747 AN: 53406

Middle Eastern (MID) AF: 0.0388 AC: 224 AN: 5768

European-Non Finnish (NFE) AF: 0.0993 AC: 110398 AN: 1112000

Other (OTH) AF: 0.0908 AC: 5483 AN: 60394

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

African (AFR) AF: 0.100 AC: 4168 AN: 41508

American (AMR) AF: 0.167 AC: 2553 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5178

South Asian (SAS) AF: 0.0590 AC: 285 AN: 4828

European-Finnish (FIN) AF: 0.125 AC: 1321 AN: 10594

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6938 AN: 68018

Other (OTH) AF: 0.0947 AC: 200 AN: 2112

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Charcot-Marie-Tooth disease dominant intermediate C (2)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.7
DANN	Benign	0.64
PhyloP100		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs699005; hg19: chr1-33245802;