4-20727315-C-G

Variant names:

• chr4-20727315-C-G
• rs767131973
• NM_001258345.3:c.721C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001258345.3(PACRGL):​c.721C>G​(p.Pro241Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,796 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P241T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PACRGL NM_001258345.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.34
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258345.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACRGL	NM_001258345.3	MANE Select	c.721C>G	p.Pro241Ala	missense	Exon 9 of 9	NP_001245274.1	Q8N7B6-1
	PACRGL	NM_145048.5		c.640C>G	p.Pro214Ala	missense	Exon 8 of 8	NP_659485.1	Q8N7B6-2
	PACRGL	NM_001317849.3		c.481C>G	p.Pro161Ala	missense	Exon 6 of 6	NP_001304778.1	D6RGK2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACRGL	ENST00000503585.6	TSL:2 MANE Select	c.721C>G	p.Pro241Ala	missense	Exon 9 of 9	ENSP00000423881.1	Q8N7B6-1
	PACRGL	ENST00000360916.9	TSL:1	c.640C>G	p.Pro214Ala	missense	Exon 8 of 8	ENSP00000354171.4	Q8N7B6-2
	PACRGL	ENST00000508952.5	TSL:1	n.*348C>G		non_coding_transcript_exon	Exon 8 of 8	ENSP00000425102.1	D6RBZ2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460796 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726764

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111258

Other (OTH) AF: 0.00 AC: 0 AN: 60356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.0045	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.87		Loss of disorder (P = 0.0373)
MVP		0.11
MPC		0.41
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.70
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs767131973; hg19: chr4-20728938;