rs150690731

Variant names:

• chr1-32775697-T-C
• rs150690731
• NM_003680.4:c.*284A>G

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.*284A>G		3_prime_UTR	Exon 13 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.*284A>G		3_prime_UTR	Exon 13 of 13	ENSP00000362576.4	P54577
	YARS1	ENST00000906066.1		c.*284A>G		3_prime_UTR	Exon 14 of 14	ENSP00000576125.1
	YARS1	ENST00000918766.1		c.*284A>G		3_prime_UTR	Exon 13 of 13	ENSP00000588825.1

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

African (AFR) AF: 0.0114 AC: 121 AN: 10614

American (AMR) AF: 0.000714 AC: 11 AN: 15406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10932

East Asian (EAS) AF: 0.00 AC: 0 AN: 23764

South Asian (SAS) AF: 0.000190 AC: 7 AN: 36786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1538

European-Non Finnish (NFE) AF: 0.00000476 AC: 1 AN: 209926

Other (OTH) AF: 0.000965 AC: 20 AN: 20724

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

African (AFR) AF: 0.0116 AC: 483 AN: 41558

American (AMR) AF: 0.000654 AC: 10 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00313 Hom.: 0

Bravo AF: 0.00373

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.6
DANN	Benign	0.68
PhyloP100		0.88
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

Other links and lift over

dbSNP: rs150690731; hg19: chr1-33241298;