2-60787582-T-A

Variant names:

• chr2-60787582-T-A
• NM_022894.4:c.1358T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022894.4(PAPOLG):​c.1358T>A​(p.Ile453Lys) 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: 7.67

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPOLG	NM_022894.4	c.1358T>A	p.Ile453Lys	missense_variant	Exon 15 of 22	ENST00000238714.8	NP_075045.2
PAPOLG	XM_005264500.5	c.1358T>A	p.Ile453Lys	missense_variant	Exon 15 of 21		XP_005264557.1
PAPOLG	XM_005264501.3	c.1226T>A	p.Ile409Lys	missense_variant	Exon 15 of 22		XP_005264558.1
PAPOLG	XR_007080681.1	n.1497+516T>A		intron_variant	Intron 14 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPOLG	ENST00000238714.8	c.1358T>A	p.Ile453Lys	missense_variant	Exon 15 of 22	1	NM_022894.4	ENSP00000238714.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1358T>A (p.I453K) alteration is located in exon 15 (coding exon 15) of the PAPOLG gene. This alteration results from a T to A substitution at nucleotide position 1358, causing the isoleucine (I) at amino acid position 453 to be replaced by a lysine (K). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	-0.0043	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;.
Vest4		0.54
MutPred		0.54		Loss of stability (P = 9e-04);.;
MVP		0.50
MPC		1.8
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-61014717;