Genetic Variant NM_020144.5:c.1843G>A (chr7-4859968-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020144.5(PAPOLB):c.1843G>A(p.Val615Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,613,868 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

PAPOLB
NM_020144.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.19

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025458902).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPOLB	NM_020144.5 link	c.1843G>A	p.Val615Ile	missense_variant	Exon 1 of 1	ENST00000404991.2	NP_064529.4	Q9NRJ5A4D1Z6
RADIL	NM_018059.5 link	c.535+17637G>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.1843G>A	p.Val615Ile	missense_variant	Exon 1 of 1	6	NM_020144.5	ENSP00000384700.2	Q9NRJ5
RADIL	ENST00000399583.4 link	c.535+17637G>A		intron_variant	Intron 2 of 14	5	NM_018059.5	ENSP00000382492.3	Q96JH8-4
RADIL	ENST00000445392.5 link	n.535+17637G>A		intron_variant	Intron 2 of 14	5		ENSP00000413403.1	F8WEM1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000212

AC:

AN:

249724

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135438

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00119

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:

0.0000972

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461690

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000177

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000983

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00191

Alfa

AF:

0.0000554

Hom.:

Bravo

AF:

0.000219

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1843G>A (p.V615I) 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 1843, causing the valine (V) at amino acid position 615 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

-0.44

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.81

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.70

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.83

M_CAP

Benign

0.0048

MetaRNN

Benign

0.025

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.29

REVEL

Benign

0.12

Sift4G

Benign

0.28

Polyphen

0.0030

Vest4

0.15

MVP

0.51

MPC

0.084

ClinPred

0.032

GERP RS

2.6

gMVP

0.071

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