4-20713436-A-T

Variant summary

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

The NM_001258345.3(PACRGL):c.506A>T(p.His169Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PACRGL NM_001258345.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PACRGL	NM_001258345.3	c.506A>T	p.His169Leu	missense_variant	7/9	ENST00000503585.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PACRGL	ENST00000503585.6	c.506A>T	p.His169Leu	missense_variant	7/9	2	NM_001258345.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jun 05, 2023

The c.506A>T (p.H169L) alteration is located in exon 7 (coding exon 6) of the PACRGL gene. This alteration results from a A to T substitution at nucleotide position 506, causing the histidine (H) at amino acid position 169 to be replaced by a leucine (L). 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	0.27
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;T;.;.;.;.;T;.;.;.;.;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;.;.;T;T;D;D;D;T;.;D;D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.4	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.69	T;T;T;T;D;D;T;T;T;D;T;T;T
Sift4G	Benign	0.28	T;T;T;T;D;T;D;D;T;D;T;D;D
Polyphen		0.85	P;P;P;P;.;.;.;.;.;.;P;D;.
Vest4		0.82, 0.81, 0.92, 0.78, 0.86
MutPred		0.46		.;Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);.;.;.;.;Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;.;
MVP		0.49
MPC		0.21
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.35
gMVP		0.72

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: rs1364292464; hg19: chr4-20715059;