4-20713526-A-G

Position:

• chr4-20713526-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001258345.3(PACRGL):​c.596A>G​(p.His199Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,458,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PACRGL NM_001258345.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26513025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PACRGL	NM_001258345.3	c.596A>G	p.His199Arg	missense_variant	7/9	ENST00000503585.6	NP_001245274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PACRGL	ENST00000503585.6	c.596A>G	p.His199Arg	missense_variant	7/9	2	NM_001258345.3	ENSP00000423881	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1458404 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 725742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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

Aug 02, 2021

The c.596A>G (p.H199R) alteration is located in exon 7 (coding exon 6) of the PACRGL gene. This alteration results from a A to G substitution at nucleotide position 596, causing the histidine (H) at amino acid position 199 to be replaced by an arginine (R). 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	0.22
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.043	T;.;.;.;.;.;.;.;T;T
Eigen	Benign	0.084
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;.;.;T;D;D;T;.;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.0	M;M;M;.;.;.;.;M;.;.
MutationTaster	Benign	0.84	D;D;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N;N;N;D;N;N;D;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.65	T;T;T;D;T;T;D;T;T;T
Sift4G	Benign	0.58	T;T;T;T;T;T;T;T;T;T
Polyphen		0.074	B;B;B;.;.;.;.;B;P;.
Vest4		0.66
MutPred		0.47		Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);.;.;Gain of MoRF binding (P = 0.0115);.;Gain of MoRF binding (P = 0.0115);.;.;
MVP		0.24
MPC		0.11
ClinPred		0.44	T
GERP RS		4.4
Varity_R		0.059
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-20715149;