chr1-54758004-G-A

Variant names:

• chr1-54758004-G-A
• rs143717155
• NM_152268.4:c.1158C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_152268.4(PARS2):​c.1158C>T​(p.Ala386Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,614,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: PARS2 NM_152268.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.787
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-54758004-G-A is Benign according to our data. Variant chr1-54758004-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 381172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.787 with no splicing effect.

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.1158C>T	p.Ala386Ala	synonymous	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.1158C>T	p.Ala386Ala	synonymous	Exon 2 of 2	ENSP00000360327.3	Q7L3T8
	PARS2	ENST00000887740.1		c.1158C>T	p.Ala386Ala	synonymous	Exon 2 of 2	ENSP00000557799.1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00113 AC: 283 AN: 251346 AF XY: 0.00113

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00112 AC: 1632 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00111 AC XY: 804 AN XY: 727224

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00221 AC: 99 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00551 AC: 144 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86252

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53412

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00113 AC: 1253 AN: 1112002

Other (OTH) AF: 0.00147 AC: 89 AN: 60394

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152314 Hom.: 1 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74480

African (AFR) AF: 0.000361 AC: 15 AN: 41574

American (AMR) AF: 0.00196 AC: 30 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.00108

EpiCase AF: 0.00115

EpiControl AF: 0.00148

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	PARS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.30
DANN	Benign	0.44
PhyloP100		-0.79
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: rs143717155; hg19: chr1-55223677;