Genetic Variant NM_002669.4:c.896C>A (chr4-154540637-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002669.4(PLRG1):c.896C>A(p.Thr299Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PLRG1
NM_002669.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLRG1	NM_002669.4 link	c.896C>A	p.Thr299Lys	missense_variant	Exon 10 of 15	ENST00000499023.7	NP_002660.1	O43660-1
PLRG1	NM_001201564.2 link	c.869C>A	p.Thr290Lys	missense_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.896C>A	p.Thr299Lys	missense_variant	Exon 10 of 15	1	NM_002669.4	ENSP00000424417.1	O43660-1
PLRG1	ENST00000302078.9 link	c.869C>A	p.Thr290Lys	missense_variant	Exon 10 of 15	1		ENSP00000303191.5	O43660-2
PLRG1	ENST00000506627.5 link	n.209C>A		non_coding_transcript_exon_variant	Exon 2 of 7	5		ENSP00000425914.1	H0YA24
PLRG1	ENST00000506192.5 link	n.*409C>A		downstream_gene_variant		2		ENSP00000424616.1	B7Z982

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251334

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135830

show subpopulations

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:

0.00000137

AC:

AN:

1461252

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726970

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.896C>A (p.T299K) alteration is located in exon 10 (coding exon 10) of the PLRG1 gene. This alteration results from a C to A substitution at nucleotide position 896, causing the threonine (T) at amino acid position 299 to be replaced by a lysine (K). 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

0.63

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.1

L;.

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.97

D;D

Vest4

0.74

MutPred

0.47

Gain of solvent accessibility (P = 0.0156);.;

MVP

0.63

MPC

2.3

ClinPred

0.97

GERP RS

5.7

Varity_R

0.89

gMVP

0.75

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

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