Genetic Variant NM_020144.5:c.1461G>A (chr7-4860350-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020144.5(PAPOLB):c.1461G>A(p.Met487Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PAPOLB
NM_020144.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.40

Variant links:

Genes affected

PAPOLB (HGNC:15970): (poly(A) polymerase beta) Predicted to enable polynucleotide adenylyltransferase activity. Predicted to be involved in mRNA polyadenylation. Predicted to be located in endoplasmic reticulum. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

PAPOLB links:

RADIL (HGNC:22226): (Rap associating with DIL domain) Predicted to enable GTPase binding activity. Acts upstream of or within substrate adhesion-dependent cell spreading. Located in microtubule. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

RADIL links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13570625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPOLB	NM_020144.5 link	c.1461G>A	p.Met487Ile	missense_variant	Exon 1 of 1	ENST00000404991.2	NP_064529.4	Q9NRJ5A4D1Z6
RADIL	NM_018059.5 link	c.535+17255G>A		intron_variant	Intron 2 of 14	ENST00000399583.4	NP_060529.4	Q96JH8-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAPOLB	ENST00000404991.2 link	c.1461G>A	p.Met487Ile	missense_variant	Exon 1 of 1	6	NM_020144.5	ENSP00000384700.2	Q9NRJ5
RADIL	ENST00000399583.4 link	c.535+17255G>A		intron_variant	Intron 2 of 14	5	NM_018059.5	ENSP00000382492.3	Q96JH8-4
RADIL	ENST00000445392.5 link	n.535+17255G>A		intron_variant	Intron 2 of 14	5		ENSP00000413403.1	F8WEM1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727110

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1461G>A (p.M487I) alteration is located in exon 1 (coding exon 1) of the PAPOLB gene. This alteration results from a G to A substitution at nucleotide position 1461, causing the methionine (M) at amino acid position 487 to be replaced by an isoleucine (I). 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

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.96

Eigen

Benign

-0.021

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0069

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.87

PrimateAI

Benign

0.36

REVEL

Benign

0.040

Sift4G

Benign

0.43

Polyphen

0.029

Vest4

0.29

MVP

0.54

MPC

0.15

ClinPred

0.39

GERP RS

4.5

gMVP

0.21

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over