rs74467041

Variant names:

• chr1-54757495-A-C
• rs74467041
• NM_152268.4:c.*239T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152268.4(PARS2):​c.*239T>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 0.0158 in 409,680 control chromosomes in the GnomAD database, including 386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (74 hom., cov: 32)
  • Exomes 𝑓: 0.018 (312 hom.)
• Consequence: PARS2 NM_152268.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.355
• Publications: 0 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=-0.87).
• BP6: Variant 1-54757495-A-C is Benign according to our data. Variant chr1-54757495-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1189621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

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.*239T>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.*239T>G		3_prime_UTR	Exon 2 of 2	ENSP00000360327.3	Q7L3T8
	PARS2	ENST00000887740.1		c.*239T>G		3_prime_UTR	Exon 2 of 2	ENSP00000557799.1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1762 AN: 152198 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00671

GnomAD4 exome AF: 0.0183 AC: 4703 AN: 257364 Hom.: 312 Cov.: 0 AF XY: 0.0209 AC XY: 2778 AN XY: 132920

African (AFR) AF: 0.0134 AC: 102 AN: 7624

American (AMR) AF: 0.00181 AC: 16 AN: 8824

Ashkenazi Jewish (ASJ) AF: 0.00221 AC: 20 AN: 9058

East Asian (EAS) AF: 0.143 AC: 2758 AN: 19282

South Asian (SAS) AF: 0.103 AC: 1630 AN: 15902

European-Finnish (FIN) AF: 0.0000578 AC: 1 AN: 17300

Middle Eastern (MID) AF: 0.00244 AC: 3 AN: 1230

European-Non Finnish (NFE) AF: 0.000216 AC: 35 AN: 162108

Other (OTH) AF: 0.00861 AC: 138 AN: 16036

GnomAD4 genome AF: 0.0116 AC: 1768 AN: 152316 Hom.: 74 Cov.: 32 AF XY: 0.0132 AC XY: 986 AN XY: 74492

African (AFR) AF: 0.0143 AC: 593 AN: 41566

American (AMR) AF: 0.00314 AC: 48 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.103 AC: 535 AN: 5188

South Asian (SAS) AF: 0.115 AC: 553 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68026

Other (OTH) AF: 0.00996 AC: 21 AN: 2108

Alfa AF: 0.00534 Hom.: 0

Bravo AF: 0.00932

Asia WGS AF: 0.109 AC: 377 AN: 3478

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	-0.87
CADD	Benign	1.8
DANN	Benign	0.74
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74467041; hg19: chr1-55223168;