chr4-154544489-T-A

Variant names:

• chr4-154544489-T-A
• rs1482713673
• NM_002669.4:c.550A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002669.4(PLRG1):​c.550A>T​(p.Thr184Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. T184A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLRG1 NM_002669.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.26
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3048502).

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.550A>T	p.Thr184Ser	missense	Exon 7 of 15	NP_002660.1	O43660-1
	PLRG1	NM_001201564.2		c.523A>T	p.Thr175Ser	missense	Exon 7 of 15	NP_001188493.1	O43660-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLRG1	ENST00000499023.7	TSL:1 MANE Select	c.550A>T	p.Thr184Ser	missense	Exon 7 of 15	ENSP00000424417.1	O43660-1
	PLRG1	ENST00000302078.9	TSL:1	c.523A>T	p.Thr175Ser	missense	Exon 7 of 15	ENSP00000303191.5	O43660-2
	PLRG1	ENST00000951251.1		c.550A>T	p.Thr184Ser	missense	Exon 7 of 16	ENSP00000621310.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460776 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726836

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111026

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.078
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.051
Sift	Benign	0.57	T
Sift4G	Benign	0.60	T
Polyphen		0.0060	B
Vest4		0.33
MutPred		0.34		Loss of glycosylation at T184 (P = 0.0375)
MVP		0.64
MPC		0.25
ClinPred		0.90	D
GERP RS		4.8
Varity_R		0.28
gMVP		0.17
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs1482713673; hg19: chr4-155465641;