2-60782680-A-ATTTTTT

Variant names:

• chr2-60782680-A-ATTTTTT
• NM_022894.4:c.1028-3_1028-2insTTTTTT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_022894.4(PAPOLG):​c.1028-3_1028-2insTTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000001 in 998,084 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAPOLG NM_022894.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.343

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 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: tttttttaatttttttttAGgtc. 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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPOLG	NM_022894.4	c.1028-3_1028-2insTTTTTT		splice_acceptor_variant, intron_variant	Intron 11 of 21	ENST00000238714.8	NP_075045.2
PAPOLG	XM_005264500.5	c.1028-3_1028-2insTTTTTT		splice_acceptor_variant, intron_variant	Intron 11 of 20		XP_005264557.1
PAPOLG	XM_005264501.3	c.896-3_896-2insTTTTTT		splice_acceptor_variant, intron_variant	Intron 11 of 21		XP_005264558.1
PAPOLG	XR_007080681.1	n.1239-3_1239-2insTTTTTT		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	c.1028-6_1028-5insTTTTTT		splice_region_variant, intron_variant	Intron 11 of 21	1	NM_022894.4	ENSP00000238714.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 8 AN: 85774 Hom.: 0 Cov.: 24 FAILED QC

Gnomad AFR AF: 0.0000460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000332

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000244

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000944

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000100 AC: 1 AN: 998084 Hom.: 0 Cov.: 43 AF XY: 0.00000203 AC XY: 1 AN XY: 491648

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: 0.00000124

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000933 AC: 8 AN: 85774 Hom.: 0 Cov.: 24 AF XY: 0.0000491 AC XY: 2 AN XY: 40764

Gnomad4 AFR AF: 0.0000460

Gnomad4 AMR AF: 0.000126

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000332

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000244

Gnomad4 NFE AF: 0.0000944

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr2-61009815;