Genetic Variant PLRG1:p.Arg313Gln (chr4-154540595-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_002669.4(PLRG1):c.938G>A(p.Arg313Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,596,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

PLRG1
NM_002669.4 missense, splice_region

Scores

Splicing: ADA: 0.9545

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

PLRG1 (HGNC:9089): (pleiotropic regulator 1) This gene encodes a core component of the cell division cycle 5-like (CDC5L) complex. The CDC5L complex is part of the spliceosome and is required for pre-mRNA splicing. The encoded protein plays a critical role in alternative splice site selection. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

PLRG1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLRG1	NM_002669.4 link	c.938G>A	p.Arg313Gln	missense_variant, splice_region_variant	Exon 10 of 15	ENST00000499023.7	NP_002660.1	O43660-1
PLRG1	NM_001201564.2 link	c.911G>A	p.Arg304Gln	missense_variant, splice_region_variant	Exon 10 of 15		NP_001188493.1	O43660-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLRG1	ENST00000499023.7 link	c.938G>A	p.Arg313Gln	missense_variant, splice_region_variant	Exon 10 of 15	1	NM_002669.4	ENSP00000424417.1	O43660-1
PLRG1	ENST00000302078.9 link	c.911G>A	p.Arg304Gln	missense_variant, splice_region_variant	Exon 10 of 15	1		ENSP00000303191.5	O43660-2
PLRG1	ENST00000506627.5 link	n.251G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 7	5		ENSP00000425914.1	H0YA24
PLRG1	ENST00000506192.5 link	n.*451G>A		downstream_gene_variant		2		ENSP00000424616.1	B7Z982

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000415

AC:

AN:

1444312

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

719772

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000365

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000372

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.938G>A (p.R313Q) alteration is located in exon 10 (coding exon 10) of the PLRG1 gene. This alteration results from a G to A substitution at nucleotide position 938, causing the arginine (R) at amino acid position 313 to be replaced by a glutamine (Q). 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

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

T;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.042

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.87

MVP

0.86

MPC

2.3

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Benign

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over