4-20707831-C-T

Variant names:

• chr4-20707831-C-T
• rs1161260643
• NM_001258345.3:c.236C>T

Variant summary

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

The NM_001258345.3(PACRGL):​c.236C>T​(p.Ala79Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,424 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PACRGL NM_001258345.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.93

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 rank	MANE	Protein	UniProt
PACRGL	NM_001258345.3	c.236C>T	p.Ala79Val	missense_variant	Exon 4 of 9	ENST00000503585.6	NP_001245274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PACRGL	ENST00000503585.6	c.236C>T	p.Ala79Val	missense_variant	Exon 4 of 9	2	NM_001258345.3	ENSP00000423881.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251228 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461424 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727052

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.236C>T (p.A79V) alteration is located in exon 4 (coding exon 3) of the PACRGL gene. This alteration results from a C to T substitution at nucleotide position 236, causing the alanine (A) at amino acid position 79 to be replaced by a valine (V). 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	0.14
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;T;.;.;.;T;T;.;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;.;.;D;D;D;D;D;D;.
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.0	.;M;M;M;.;.;.;.;.;.;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.5	N;N;N;N;D;D;D;D;D;N;N
REVEL	Benign	0.21
Sift	Benign	0.11	T;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.043	D;T;T;T;T;D;T;T;D;T;T
Polyphen		0.97	D;D;D;D;.;.;.;.;.;.;D
Vest4		0.74, 0.75
MutPred		0.39		.;Loss of disorder (P = 0.1069);Loss of disorder (P = 0.1069);Loss of disorder (P = 0.1069);Loss of disorder (P = 0.1069);Loss of disorder (P = 0.1069);Loss of disorder (P = 0.1069);Loss of disorder (P = 0.1069);Loss of disorder (P = 0.1069);Loss of disorder (P = 0.1069);Loss of disorder (P = 0.1069);
MVP		0.055
MPC		0.17
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.30
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1161260643; hg19: chr4-20709454;