2-60768829-C-A

Variant names:

• chr2-60768829-C-A
• NM_022894.4:c.377C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022894.4(PAPOLG):​c.377C>A​(p.Ser126Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PAPOLG NM_022894.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.683

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4239757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPOLG	NM_022894.4	c.377C>A	p.Ser126Tyr	missense_variant	Exon 5 of 22	ENST00000238714.8	NP_075045.2
PAPOLG	XM_005264500.5	c.377C>A	p.Ser126Tyr	missense_variant	Exon 5 of 21		XP_005264557.1
PAPOLG	XM_005264501.3	c.245C>A	p.Ser82Tyr	missense_variant	Exon 5 of 22		XP_005264558.1
PAPOLG	XR_007080681.1	n.588C>A		non_coding_transcript_exon_variant	Exon 5 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPOLG	ENST00000238714.8	c.377C>A	p.Ser126Tyr	missense_variant	Exon 5 of 22	1	NM_022894.4	ENSP00000238714.3
PAPOLG	ENST00000414060.5	n.245C>A		non_coding_transcript_exon_variant	Exon 5 of 21	1		ENSP00000405599.1
PAPOLG	ENST00000453839.5	n.359C>A		non_coding_transcript_exon_variant	Exon 4 of 20	1		ENSP00000414070.1
PAPOLG	ENST00000496283.5	n.457C>A		non_coding_transcript_exon_variant	Exon 5 of 19	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449028 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 721052

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: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.72	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.97	D
Vest4		0.50
MutPred		0.50		Loss of disorder (P = 0.0213);
MVP		0.52
MPC		1.8
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.86
gMVP		0.56

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: chr2-60995964;