2-60771567-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_022894.4(PAPOLG):​c.541T>G​(p.Leu181Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PAPOLG
NM_022894.4 missense

Scores

3
9
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.59
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAPOLGNM_022894.4 linkc.541T>G p.Leu181Val missense_variant Exon 7 of 22 ENST00000238714.8 NP_075045.2 Q9BWT3-1
PAPOLGXM_005264500.5 linkc.541T>G p.Leu181Val missense_variant Exon 7 of 21 XP_005264557.1 Q9BWT3-2
PAPOLGXM_005264501.3 linkc.409T>G p.Leu137Val missense_variant Exon 7 of 22 XP_005264558.1
PAPOLGXR_007080681.1 linkn.752T>G non_coding_transcript_exon_variant Exon 7 of 16

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAPOLGENST00000238714.8 linkc.541T>G p.Leu181Val missense_variant Exon 7 of 22 1 NM_022894.4 ENSP00000238714.3 Q9BWT3-1
PAPOLGENST00000414060.5 linkn.409T>G non_coding_transcript_exon_variant Exon 7 of 21 1 ENSP00000405599.1 F8WAT4
PAPOLGENST00000453839.5 linkn.474+1056T>G intron_variant Intron 5 of 19 1 ENSP00000414070.1 H7C3W0
PAPOLGENST00000496283.5 linkn.572+1056T>G intron_variant Intron 6 of 18 1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000406
AC:
1
AN:
246076
Hom.:
0
AF XY:
0.00000750
AC XY:
1
AN XY:
133330
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:
0.00000890
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1455962
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
724388
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 07, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.541T>G (p.L181V) alteration is located in exon 7 (coding exon 7) of the PAPOLG gene. This alteration results from a T to G substitution at nucleotide position 541, causing the leucine (L) at amino acid position 181 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
0.23
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.10
T
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Benign
0.013
T
MetaRNN
Pathogenic
0.76
D
MetaSVM
Benign
-0.29
T
MutationAssessor
Pathogenic
3.0
M
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-1.6
N
REVEL
Benign
0.21
Sift
Uncertain
0.017
D
Sift4G
Uncertain
0.058
T
Polyphen
0.86
P
Vest4
0.74
MutPred
0.75
Loss of disorder (P = 0.1892);
MVP
0.67
MPC
1.4
ClinPred
0.89
D
GERP RS
5.4
Varity_R
0.44
gMVP
0.71

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.

Other links and lift over

dbSNP: rs1451505978; hg19: chr2-60998702; API