rs151227410

Variant names:

• chr1-32779484-C-T
• rs151227410
• NM_003680.4:c.1374G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003680.4(YARS1):​c.1374G>A​(p.Pro458Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 1,614,200 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: YARS1 NM_003680.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.45
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-32779484-C-T is Benign according to our data. Variant chr1-32779484-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 297149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00119 (182/152306) while in subpopulation AMR AF = 0.00281 (43/15300). AF 95% confidence interval is 0.00214. There are 1 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003680.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS1	NM_003680.4	MANE Select	c.1374G>A	p.Pro458Pro	synonymous	Exon 12 of 13	NP_003671.1	P54577

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS1	ENST00000373477.9	TSL:1 MANE Select	c.1374G>A	p.Pro458Pro	synonymous	Exon 12 of 13	ENSP00000362576.4	P54577
	YARS1	ENST00000906066.1		c.1461G>A	p.Pro487Pro	synonymous	Exon 13 of 14	ENSP00000576125.1
	YARS1	ENST00000918766.1		c.1371G>A	p.Pro457Pro	synonymous	Exon 12 of 13	ENSP00000588825.1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152188 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.000947 AC: 238 AN: 251414 AF XY: 0.000765

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000390 AC: 570 AN: 1461894 Hom.: 2 Cov.: 31 AF XY: 0.000363 AC XY: 264 AN XY: 727248

African (AFR) AF: 0.00170 AC: 57 AN: 33480

American (AMR) AF: 0.00402 AC: 180 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000243 AC: 270 AN: 1112012

Other (OTH) AF: 0.000878 AC: 53 AN: 60396

GnomAD4 genome AF: 0.00119 AC: 182 AN: 152306 Hom.: 1 Cov.: 31 AF XY: 0.00118 AC XY: 88 AN XY: 74490

African (AFR) AF: 0.00221 AC: 92 AN: 41566

American (AMR) AF: 0.00281 AC: 43 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68028

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.000769 Hom.: 0

Bravo AF: 0.00145

EpiCase AF: 0.000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Charcot-Marie-Tooth disease dominant intermediate C (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	YARS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.1
DANN	Benign	0.84
PhyloP100		-1.4
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs151227410; hg19: chr1-33245085;