2-60791823-G-A

Variant names:

• chr2-60791823-G-A
• rs1384220052
• NM_022894.4:c.1459G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022894.4(PAPOLG):​c.1459G>A​(p.Val487Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAPOLG NM_022894.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022894.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPOLG	NM_022894.4	MANE Select	c.1459G>A	p.Val487Ile	missense	Exon 16 of 22	NP_075045.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPOLG	ENST00000238714.8	TSL:1 MANE Select	c.1459G>A	p.Val487Ile	missense	Exon 16 of 22	ENSP00000238714.3	Q9BWT3-1
	PAPOLG	ENST00000412217.1	TSL:1	c.463G>A	p.Val155Ile	missense	Exon 6 of 11	ENSP00000405570.1	A0A0C4DH56
	PAPOLG	ENST00000414060.5	TSL:1	n.*549G>A		non_coding_transcript_exon	Exon 15 of 21	ENSP00000405599.1	F8WAT4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.7	L
PhyloP100		10
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.14	T
Polyphen		0.010	B
Vest4		0.38
MutPred		0.67		Loss of methylation at K488 (P = 0.0592)
MVP		0.39
MPC		0.43
ClinPred		0.88	D
GERP RS		6.0
Varity_R		0.31
gMVP		0.32
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs1384220052; hg19: chr2-61018958;