1-54757589-T-C

Variant names:

• chr1-54757589-T-C
• rs112294032
• NM_152268.4:c.*145A>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_152268.4(PARS2):​c.*145A>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 0.0214 in 589,370 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (35 hom., cov: 32)
  • Exomes 𝑓: 0.022 (145 hom.)
• Consequence: PARS2 NM_152268.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0630
• Publications: 1 publications found

Genes affected

PARS2 (HGNC:30563): (prolyl-tRNA synthetase 2, mitochondrial) This gene encodes a putative member of the class II family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of proline to tRNA molecules. Mutations have been found in this gene in some patients with Alpers syndrome. [provided by RefSeq, Mar 2015]

PARS2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 75

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-54757589-T-C is Benign according to our data. Variant chr1-54757589-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1201465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0186 (2824/152164) while in subpopulation NFE AF = 0.0297 (2018/68002). AF 95% confidence interval is 0.0286. There are 35 homozygotes in GnomAd4. There are 1331 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152268.4. 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
	PARS2	NM_152268.4	MANE Select	c.*145A>G		3_prime_UTR	Exon 2 of 2	NP_689481.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARS2	ENST00000371279.4	TSL:1 MANE Select	c.*145A>G		3_prime_UTR	Exon 2 of 2	ENSP00000360327.3	Q7L3T8
	PARS2	ENST00000887740.1		c.*145A>G		3_prime_UTR	Exon 2 of 2	ENSP00000557799.1

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2824 AN: 152046 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00602

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0257

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.0223 AC: 9767 AN: 437206 Hom.: 145 Cov.: 5 AF XY: 0.0216 AC XY: 4944 AN XY: 228424

African (AFR) AF: 0.00489 AC: 60 AN: 12258

American (AMR) AF: 0.00863 AC: 144 AN: 16680

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 112 AN: 13420

East Asian (EAS) AF: 0.00 AC: 0 AN: 30410

South Asian (SAS) AF: 0.00846 AC: 346 AN: 40896

European-Finnish (FIN) AF: 0.0266 AC: 786 AN: 29556

Middle Eastern (MID) AF: 0.00874 AC: 17 AN: 1946

European-Non Finnish (NFE) AF: 0.0291 AC: 7760 AN: 266518

Other (OTH) AF: 0.0212 AC: 542 AN: 25522

GnomAD4 genome AF: 0.0186 AC: 2824 AN: 152164 Hom.: 35 Cov.: 32 AF XY: 0.0179 AC XY: 1331 AN XY: 74398

African (AFR) AF: 0.00600 AC: 249 AN: 41490

American (AMR) AF: 0.0111 AC: 169 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4828

European-Finnish (FIN) AF: 0.0257 AC: 272 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0297 AC: 2018 AN: 68002

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0238 Hom.: 13

Bravo AF: 0.0167

Asia WGS AF: 0.00289 AC: 11 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.6
DANN	Benign	0.46
PhyloP100		0.063
Mutation Taster		=100/0	polymorphism

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: rs112294032; hg19: chr1-55223262;