4-20704716-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001258345.3(PACRGL):c.109C>A(p.Gln37Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PACRGL NM_001258345.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13067129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PACRGL	NM_001258345.3	c.109C>A	p.Gln37Lys	missense_variant	3/9	ENST00000503585.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PACRGL	ENST00000503585.6	c.109C>A	p.Gln37Lys	missense_variant	3/9	2	NM_001258345.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

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

Sep 14, 2023

The c.109C>A (p.Q37K) alteration is located in exon 3 (coding exon 2) of the PACRGL gene. This alteration results from a C to A substitution at nucleotide position 109, causing the glutamine (Q) at amino acid position 37 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	Benign	0.071
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.024	T;T;.;.;.;.;T;T;.;.;T;.;.;.;.;.;.;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D;D;.;.;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.70	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;D;N;N;N;N;D;D;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.086	T;T;T;T;T;D;T;T;T;D;T;D;T;T;D;D;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;D;T;T;T;D;T;T;T;T;D;D;T;T;T
Polyphen		0.69	P;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;B;B;.
Vest4		0.32, 0.34, 0.38, 0.45, 0.29, 0.41
MutPred		0.19		.;Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);Gain of methylation at Q37 (P = 0.0074);
MVP		0.048
MPC		0.20
ClinPred		0.38	T
GERP RS		5.7
Varity_R		0.14
gMVP		0.45

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: rs1471432351; hg19: chr4-20706339;