2-60782680-A-ATTTTTTTTTTT

Variant names:

• chr2-60782680-A-ATTTTTTTTTTT
• rs1553378906
• NM_022894.4:c.1028-3_1028-2insTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_022894.4(PAPOLG):​c.1028-3_1028-2insTTTTTTTTTTT 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 998,086 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00021 (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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 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: ttaattttttttttttttAGgtc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022894.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPOLG	NM_022894.4	MANE Select	c.1028-3_1028-2insTTTTTTTTTTT		splice_acceptor intron	N/A	NP_075045.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPOLG	ENST00000238714.8	TSL:1 MANE Select	c.1028-6_1028-5insTTTTTTTTTTT		splice_region intron	N/A	ENSP00000238714.3	Q9BWT3-1
	PAPOLG	ENST00000412217.1	TSL:1	c.32-6_32-5insTTTTTTTTTTT		splice_region intron	N/A	ENSP00000405570.1	A0A0C4DH56
	PAPOLG	ENST00000414060.5	TSL:1	n.*118-6_*118-5insTTTTTTTTTTT		splice_region intron	N/A	ENSP00000405599.1	F8WAT4

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 18 AN: 85778 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000921

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000378

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000976

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000212

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000100 AC: 1 AN: 998086 Hom.: 0 Cov.: 43 AF XY: 0.00000203 AC XY: 1 AN XY: 491648

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19782

American (AMR) AF: 0.00 AC: 0 AN: 15708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15030

East Asian (EAS) AF: 0.00 AC: 0 AN: 25122

South Asian (SAS) AF: 0.00 AC: 0 AN: 41046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2792

European-Non Finnish (NFE) AF: 0.00000124 AC: 1 AN: 805752

Other (OTH) AF: 0.00 AC: 0 AN: 38932

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000210 AC: 18 AN: 85778 Hom.: 0 Cov.: 24 AF XY: 0.000270 AC XY: 11 AN XY: 40770

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000921 AC: 2 AN: 21722

American (AMR) AF: 0.000378 AC: 3 AN: 7938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2142

East Asian (EAS) AF: 0.00 AC: 0 AN: 3012

South Asian (SAS) AF: 0.00 AC: 0 AN: 2580

European-Finnish (FIN) AF: 0.000976 AC: 4 AN: 4100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 174

European-Non Finnish (NFE) AF: 0.000212 AC: 9 AN: 42366

Other (OTH) AF: 0.00 AC: 0 AN: 1166

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000000222045), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553378906; hg19: chr2-61009815;