2-60782680-A-ATTTTTTTTTTGT

Variant names:

• chr2-60782680-A-ATTTTTTTTTTGT
• rs1553378906
• NM_022894.4:c.1028-3_1028-2insTTTTTTTGTTTT

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_1028-2insTTTTTTTGTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 85,792 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 0.000012 (0 hom., cov: 24)
• 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: taattttttttttgttttAGgtc. 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_1028-2insTTTTTTTGTTTT		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_1028-5insTTTTTTTTTTGT		splice_region intron	N/A	ENSP00000238714.3	Q9BWT3-1
	PAPOLG	ENST00000412217.1	TSL:1	c.32-6_32-5insTTTTTTTTTTGT		splice_region intron	N/A	ENSP00000405570.1	A0A0C4DH56
	PAPOLG	ENST00000414060.5	TSL:1	n.*118-6_*118-5insTTTTTTTTTTGT		splice_region intron	N/A	ENSP00000405599.1	F8WAT4

Frequencies

GnomAD3 genomes AF: 0.0000117 AC: 1 AN: 85792 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 43

GnomAD4 genome AF: 0.0000117 AC: 1 AN: 85792 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 40776

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

African (AFR) AF: 0.0000460 AC: 1 AN: 21726

American (AMR) AF: 0.00 AC: 0 AN: 7940

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: 0.00 AC: 0 AN: 4102

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 42372

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), 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;