2-60771567-T-G

Variant names:

• chr2-60771567-T-G
• rs1451505978
• NM_022894.4:c.541T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

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]

ACMG classification

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
PAPOLG	NM_022894.4	c.541T>G	p.Leu181Val	missense_variant	Exon 7 of 22	ENST00000238714.8	NP_075045.2
PAPOLG	XM_005264500.5	c.541T>G	p.Leu181Val	missense_variant	Exon 7 of 21		XP_005264557.1
PAPOLG	XM_005264501.3	c.409T>G	p.Leu137Val	missense_variant	Exon 7 of 22		XP_005264558.1
PAPOLG	XR_007080681.1	n.752T>G		non_coding_transcript_exon_variant	Exon 7 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPOLG	ENST00000238714.8	c.541T>G	p.Leu181Val	missense_variant	Exon 7 of 22	1	NM_022894.4	ENSP00000238714.3
PAPOLG	ENST00000414060.5	n.409T>G		non_coding_transcript_exon_variant	Exon 7 of 21	1		ENSP00000405599.1
PAPOLG	ENST00000453839.5	n.474+1056T>G		intron_variant	Intron 5 of 19	1		ENSP00000414070.1
PAPOLG	ENST00000496283.5	n.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

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

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

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

Other links and lift over

dbSNP: rs1451505978; hg19: chr2-60998702;