Variant 2-60768871-A-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_022894.4(PAPOLG):c.419A>T(p.Asp140Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,442,858 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000027 ( 1 hom. )

Consequence

PAPOLG
NM_022894.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52

Variant links:

Genes affected

PAPOLG (HGNC:14982): (poly(A) polymerase gamma) This gene encodes a member of the poly(A) polymerase family which catalyzes template-independent extension of the 3' end of a DNA/RNA strand. This enzyme shares 60% identity to the well characterized poly(A) polymerase II (PAPII) at the amino acid level. These two enzymes have similar organization of structural and functional domains. This enzyme is exclusively localized in the nucleus and exhibits both nonspecific and CPSF (cleavage and polyadenylation specificity factor)/AAUAAA-dependent polyadenylation activity. This gene is located on chromosome 2 in contrast to the PAPII gene, which is located on chromosome 14. [provided by RefSeq, Jul 2008]

PAPOLG 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=0.17566445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPOLG	NM_022894.4 link	c.419A>T	p.Asp140Val	missense_variant	Exon 5 of 22	ENST00000238714.8	NP_075045.2	Q9BWT3-1
PAPOLG	XM_005264500.5 link	c.419A>T	p.Asp140Val	missense_variant	Exon 5 of 21		XP_005264557.1	Q9BWT3-2
PAPOLG	XM_005264501.3 link	c.287A>T	p.Asp96Val	missense_variant	Exon 5 of 22		XP_005264558.1
PAPOLG	XR_007080681.1 link	n.630A>T		non_coding_transcript_exon_variant	Exon 5 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAPOLG	ENST00000238714.8 link	c.419A>T	p.Asp140Val	missense_variant	Exon 5 of 22	1	NM_022894.4	ENSP00000238714.3	Q9BWT3-1
PAPOLG	ENST00000414060.5 link	n.287A>T		non_coding_transcript_exon_variant	Exon 5 of 21	1		ENSP00000405599.1	F8WAT4
PAPOLG	ENST00000453839.5 link	n.401A>T		non_coding_transcript_exon_variant	Exon 4 of 20	1		ENSP00000414070.1	H7C3W0
PAPOLG	ENST00000496283.5 link	n.499A>T		non_coding_transcript_exon_variant	Exon 5 of 19	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000418

AC:

AN:

238980

Hom.:

AF XY:

0.0000541

AC XY:

AN XY:

129278

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000920

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000270

AC:

AN:

1442858

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

718074

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:

0.0000300

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.419A>T (p.D140V) alteration is located in exon 5 (coding exon 5) of the PAPOLG gene. This alteration results from a A to T substitution at nucleotide position 419, causing the aspartic acid (D) at amino acid position 140 to be replaced by a valine (V). 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

0.15

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.023

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.26

Sift

Uncertain

0.020

Sift4G

Uncertain

0.023

Polyphen

0.0050

Vest4

0.35

MutPred

0.50

Loss of ubiquitination at K135 (P = 0.0508);

MVP

0.58

MPC

1.1

ClinPred

0.29

GERP RS

5.6

Varity_R

0.58

gMVP

0.45

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