1-32775529-CCCTTT-C

Variant names:

• chr1-32775529-CCCTTT-C
• rs142185532
• NM_003680.4:c.*447_*451delAAAGG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_003680.4(YARS1):​c.*447_*451delAAAGG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 179,400 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0092 (12 hom., cov: 32)
  • Exomes 𝑓: 0.011 (6 hom.)
• Consequence: YARS1 NM_003680.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.62
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 1-32775529-CCCTTT-C is Benign according to our data. Variant chr1-32775529-CCCTTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 297138.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00923 (1405/152298) while in subpopulation SAS AF = 0.0325 (157/4826). AF 95% confidence interval is 0.0284. There are 12 homozygotes in GnomAd4. There are 762 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.*447_*451delAAAGG		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.*447_*451delAAAGG		3_prime_UTR	Exon 13 of 13	ENSP00000362576.4	P54577
	YARS1	ENST00000906066.1		c.*447_*451delAAAGG		3_prime_UTR	Exon 14 of 14	ENSP00000576125.1
	YARS1	ENST00000918766.1		c.*447_*451delAAAGG		3_prime_UTR	Exon 13 of 13	ENSP00000588825.1

Frequencies

GnomAD3 genomes AF: 0.00922 AC: 1403 AN: 152180 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.0108 AC: 293 AN: 27102 Hom.: 6 AF XY: 0.0131 AC XY: 186 AN XY: 14172

African (AFR) AF: 0.00 AC: 0 AN: 764

American (AMR) AF: 0.00503 AC: 15 AN: 2984

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 6 AN: 462

East Asian (EAS) AF: 0.00 AC: 0 AN: 1828

South Asian (SAS) AF: 0.0350 AC: 110 AN: 3144

European-Finnish (FIN) AF: 0.0154 AC: 18 AN: 1172

Middle Eastern (MID) AF: 0.0139 AC: 1 AN: 72

European-Non Finnish (NFE) AF: 0.00810 AC: 125 AN: 15428

Other (OTH) AF: 0.0144 AC: 18 AN: 1248

GnomAD4 genome AF: 0.00923 AC: 1405 AN: 152298 Hom.: 12 Cov.: 32 AF XY: 0.0102 AC XY: 762 AN XY: 74476

African (AFR) AF: 0.00159 AC: 66 AN: 41564

American (AMR) AF: 0.00608 AC: 93 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

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

South Asian (SAS) AF: 0.0325 AC: 157 AN: 4826

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0118 AC: 801 AN: 68020

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.0113 Hom.: 1

Bravo AF: 0.00743

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth, Intermediate (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142185532; hg19: chr1-33241130;