4-154537357-G-C

Position:

• chr4-154537357-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002669.4(PLRG1):​c.1414C>G​(p.Gln472Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLRG1 NM_002669.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.75

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26731426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLRG1	NM_002669.4	c.1414C>G	p.Gln472Glu	missense_variant	14/15	ENST00000499023.7	NP_002660.1
PLRG1	NM_001201564.2	c.1387C>G	p.Gln463Glu	missense_variant	14/15		NP_001188493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLRG1	ENST00000499023.7	c.1414C>G	p.Gln472Glu	missense_variant	14/15	1	NM_002669.4	ENSP00000424417	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460998 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726796

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2023

The c.1414C>G (p.Q472E) alteration is located in exon 14 (coding exon 14) of the PLRG1 gene. This alteration results from a C to G substitution at nucleotide position 1414, causing the glutamine (Q) at amino acid position 472 to be replaced by a glutamic acid (E). 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	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.10	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.58	P;B
Vest4		0.41
MutPred		0.40		Gain of disorder (P = 0.0665);.;
MVP		0.64
MPC		1.2
ClinPred		0.63	D
GERP RS		5.6
Varity_R		0.29
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-155458509;