Genetic Variant NM_022894.4:c.1028-3dupT (chr2-60782680-A-AT) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_022894.4(PAPOLG):c.1028-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000401 in 998,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000023 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0000040 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PAPOLG
NM_022894.4 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.343

Variant links:

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]

PAPOLG links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.038444143 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of 0 (no position change), new splice context is: ttttttttttttaattttAGgtc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PAPOLG	NM_022894.4 link	c.1028-3dupT	splice_acceptor_variant, intron_variant	Intron 11 of 21	ENST00000238714.8	NP_075045.2	Q9BWT3-1
PAPOLG	XM_005264500.5 link	c.1028-3dupT	splice_acceptor_variant, intron_variant	Intron 11 of 20		XP_005264557.1	Q9BWT3-2
PAPOLG	XM_005264501.3 link	c.896-3dupT	splice_acceptor_variant, intron_variant	Intron 11 of 21		XP_005264558.1
PAPOLG	XR_007080681.1 link	n.1239-3dupT	splice_acceptor_variant, intron_variant	Intron 11 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPOLG	ENST00000238714.8 link	c.1028-6_1028-5insT		splice_region_variant, intron_variant	Intron 11 of 21	1	NM_022894.4	ENSP00000238714.3		Q9BWT3-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

85786

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000126

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000236

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000401

AC:

AN:

998022

Hom.:

Cov.:

AF XY:

0.00000203

AC XY:

AN XY:

491622

show subpopulations

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:

0.00000496

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000233

AC:

AN:

85800

Hom.:

Cov.:

AF XY:

0.0000245

AC XY:

AN XY:

40800

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000126

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000236

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over