4-20712842-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001258345.3(PACRGL):​c.421G>A​(p.Glu141Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000166 in 1,603,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

PACRGL
NM_001258345.3 missense

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.94
Variant links:
Genes affected
PACRGL (HGNC:28442): (parkin coregulated like)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PACRGLNM_001258345.3 linkuse as main transcriptc.421G>A p.Glu141Lys missense_variant 6/9 ENST00000503585.6 NP_001245274.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PACRGLENST00000503585.6 linkuse as main transcriptc.421G>A p.Glu141Lys missense_variant 6/92 NM_001258345.3 ENSP00000423881 P1Q8N7B6-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152114
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000965
AC:
24
AN:
248742
Hom.:
0
AF XY:
0.0000669
AC XY:
9
AN XY:
134520
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000148
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000463
Gnomad NFE exome
AF:
0.000151
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.000176
AC:
255
AN:
1451382
Hom.:
1
Cov.:
30
AF XY:
0.000148
AC XY:
107
AN XY:
721738
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000136
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000755
Gnomad4 NFE exome
AF:
0.000213
Gnomad4 OTH exome
AF:
0.000150
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152232
Hom.:
0
Cov.:
31
AF XY:
0.0000537
AC XY:
4
AN XY:
74424
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000741
AC:
9

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 06, 2023The c.421G>A (p.E141K) alteration is located in exon 6 (coding exon 5) of the PACRGL gene. This alteration results from a G to A substitution at nucleotide position 421, causing the glutamic acid (E) at amino acid position 141 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.28
T;T;.;.;T;.;.;.;T;T
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D;D;.;.;D;D;D;.;D;D
M_CAP
Benign
0.020
T
MetaRNN
Pathogenic
0.76
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Uncertain
2.9
.;M;M;M;.;.;.;M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-3.2
D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0060
D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0080
D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;.;.;.;D;D;.
Vest4
0.81, 0.82, 0.76, 0.79
MVP
0.081
MPC
0.42
ClinPred
0.85
D
GERP RS
5.9
Varity_R
0.63
gMVP
0.79

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200118578; hg19: chr4-20714465; API