rs1180947

Variant names:

• chr1-54763681-A-G
• rs1180947
• NM_152268.4:c.-30+780T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_152268.4(PARS2):​c.-30+780T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 152,338 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.027 (100 hom., cov: 33)
• Consequence: PARS2 NM_152268.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.710
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0266 (4051/152338) while in subpopulation SAS AF = 0.0435 (210/4830). AF 95% confidence interval is 0.0387. There are 100 homozygotes in GnomAd4. There are 1927 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 100 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARS2	NM_152268.4	c.-30+780T>C		intron_variant	Intron 1 of 1	ENST00000371279.4	NP_689481.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARS2	ENST00000371279.4	c.-30+780T>C		intron_variant	Intron 1 of 1	1	NM_152268.4	ENSP00000360327.3

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4055 AN: 152220 Hom.: 100 Cov.: 33

Gnomad AFR AF: 0.00673

Gnomad AMI AF: 0.0571

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0402

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0266 AC: 4051 AN: 152338 Hom.: 100 Cov.: 33 AF XY: 0.0259 AC XY: 1927 AN XY: 74498

African (AFR) AF: 0.00671 AC: 279 AN: 41596

American (AMR) AF: 0.0229 AC: 350 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0435 AC: 210 AN: 4830

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10612

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0397 AC: 2702 AN: 68022

Other (OTH) AF: 0.0402 AC: 85 AN: 2114

Alfa AF: 0.0327 Hom.: 34

Bravo AF: 0.0248

Asia WGS AF: 0.0190 AC: 66 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.74
DANN	Benign	0.24
PhyloP100		-0.71
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: rs1180947; hg19: chr1-55229354;