4-154537434-T-C

Position:

• chr4-154537434-T-C

Variant summary

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

The NM_002669.4(PLRG1):​c.1337A>G​(p.Asn446Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: PLRG1 NM_002669.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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=0.38197243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLRG1	NM_002669.4	c.1337A>G	p.Asn446Ser	missense_variant	14/15	ENST00000499023.7	NP_002660.1
PLRG1	NM_001201564.2	c.1310A>G	p.Asn437Ser	missense_variant	14/15		NP_001188493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLRG1	ENST00000499023.7	c.1337A>G	p.Asn446Ser	missense_variant	14/15	1	NM_002669.4	ENSP00000424417	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Oct 26, 2022

The c.1337A>G (p.N446S) alteration is located in exon 14 (coding exon 14) of the PLRG1 gene. This alteration results from a A to G substitution at nucleotide position 1337, causing the asparagine (N) at amino acid position 446 to be replaced by a serine (S). 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	0.17
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.81	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.39
Sift	Benign	0.21	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.25	B;D
Vest4		0.59
MutPred		0.35		Gain of sheet (P = 0.1208);.;
MVP		0.79
MPC		1.9
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.44
gMVP		0.42

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: chr4-155458586;