2-60793628-A-G

Position:

• chr2-60793628-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022894.4(PAPOLG):​c.1681A>G​(p.Asn561Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAPOLG NM_022894.4 missense, splice_region
• Scores: Splicing: ADA: 0.001869
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060082108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAPOLG	NM_022894.4	c.1681A>G	p.Asn561Asp	missense_variant, splice_region_variant	18/22	ENST00000238714.8	NP_075045.2
PAPOLG	XM_005264500.5	c.1681A>G	p.Asn561Asp	missense_variant, splice_region_variant	18/21		XP_005264557.1
PAPOLG	XM_005264501.3	c.1549A>G	p.Asn517Asp	missense_variant, splice_region_variant	18/22		XP_005264558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAPOLG	ENST00000238714.8	c.1681A>G	p.Asn561Asp	missense_variant, splice_region_variant	18/22	1	NM_022894.4	ENSP00000238714	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.1681A>G (p.N561D) alteration is located in exon 18 (coding exon 18) of the PAPOLG gene. This alteration results from a A to G substitution at nucleotide position 1681, causing the asparagine (N) at amino acid position 561 to be replaced by an aspartic acid (D). 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	0.077
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.068
Sift	Benign	0.16	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0	B;.
Vest4		0.083
MVP		0.40
MPC		0.13
ClinPred		0.39	T
GERP RS		3.2
Varity_R		0.087
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.034
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: rs1463885031; hg19: chr2-61020763;