Genetic Variant PLRG1:p.Ala161Glu (chr4-154545846-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002669.4(PLRG1):c.482C>A(p.Ala161Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. A161V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PLRG1
NM_002669.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0170

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.053937584).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002669.4. 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
	PLRG1	NM_002669.4	MANE Select	c.482C>A	p.Ala161Glu	missense	Exon 6 of 15	NP_002660.1	O43660-1
	PLRG1	NM_001201564.2		c.455C>A	p.Ala152Glu	missense	Exon 6 of 15	NP_001188493.1	O43660-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLRG1	ENST00000499023.7	TSL:1 MANE Select	c.482C>A	p.Ala161Glu	missense	Exon 6 of 15	ENSP00000424417.1	O43660-1
PLRG1	ENST00000302078.9	TSL:1	c.455C>A	p.Ala152Glu	missense	Exon 6 of 15	ENSP00000303191.5	O43660-2
PLRG1	ENST00000951251.1		c.482C>A	p.Ala161Glu	missense	Exon 6 of 16	ENSP00000621310.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450578

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33150

American (AMR)

AF:

0.00

AC:

AN:

44248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26024

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.00

AC:

AN:

85756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1102708

Other (OTH)

AF:

0.00

AC:

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.12

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.68

M_CAP

Benign

0.033

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.55

PhyloP100

0.017

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.010

REVEL

Benign

0.039

Sift

Benign

0.53

Sift4G

Benign

0.41

Polyphen

0.013

Vest4

0.18

MutPred

0.25

Gain of sheet (P = 0.0477)

MVP

0.39

MPC

0.31

ClinPred

0.024

GERP RS

-3.7

Varity_R

0.028

gMVP

0.17

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over