4-20704723-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001258345.3(PACRGL):c.116G>A(p.Ser39Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: PACRGL NM_001258345.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

Genes affected

PACRGL (HGNC:28442): (parkin coregulated like)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029059142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PACRGL	NM_001258345.3	c.116G>A	p.Ser39Asn	missense_variant	3/9	ENST00000503585.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PACRGL	ENST00000503585.6	c.116G>A	p.Ser39Asn	missense_variant	3/9	2	NM_001258345.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000796 AC: 20 AN: 251354 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461762 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.116G>A (p.S39N) alteration is located in exon 3 (coding exon 2) of the PACRGL gene. This alteration results from a G to A substitution at nucleotide position 116, causing the serine (S) at amino acid position 39 to be replaced by an asparagine (N). 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	Benign	0.070
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.026	T;T;.;.;.;.;T;T;.;.;T;.;.;.;.;.;.;T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.65	T;T;.;.;T;T;T;T;T;T;T;T;T;T;T;T;.;T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.029	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;D;N;N;N;N;N;D;N;N;N
REVEL	Benign	0.099
Sift	Benign	0.030	D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.099	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.034	B;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;B;B;.
Vest4		0.18, 0.22, 0.21, 0.26, 0.22, 0.22
MutPred		0.15		.;Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);Loss of phosphorylation at S39 (P = 0.0215);
MVP		0.014
MPC		0.065
ClinPred		0.080	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.073
gMVP		0.31

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

Other links and lift over

dbSNP: rs780926922; hg19: chr4-20706346;