2-60782680-A-ATTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chr2-60782680-A-ATTTTTTTTTTTTTTTTTTTTTTT
• rs1553378906
• NM_022894.4:c.1028-3_1028-2insTTTTTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PVS1_Moderate BP6_Moderate

The NM_022894.4(PAPOLG):​c.1028-3_1028-2insTTTTTTTTTTTTTTTTTTTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 24)
  • Failed GnomAD Quality Control
• Consequence: PAPOLG NM_022894.4 splice_acceptor, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 0 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 14, offset of 0 (no position change), new splice context is: ttttttttttttttttttAGgtc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 2-60782680-A-ATTTTTTTTTTTTTTTTTTTTTTT is Benign according to our data. Variant chr2-60782680-A-ATTTTTTTTTTTTTTTTTTTTTTT is described in ClinVar as Likely_benign. ClinVar VariationId is 710413.Status of the report is criteria_provided_single_submitter, 1 stars.

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_1028-2insTTTTTTTTTTTTTTTTTTTTTTT		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_1028-5insTTTTTTTTTTTTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000238714.3	Q9BWT3-1
	PAPOLG	ENST00000412217.1	TSL:1	c.32-6_32-5insTTTTTTTTTTTTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000405570.1	A0A0C4DH56
	PAPOLG	ENST00000414060.5	TSL:1	n.*118-6_*118-5insTTTTTTTTTTTTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000405599.1	F8WAT4

Frequencies

GnomAD3 genomes AF: 0.000175 AC: 15 AN: 85786 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000184

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: 0.000488

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000189

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 43

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000175 AC: 15 AN: 85786 Hom.: 0 Cov.: 24 AF XY: 0.000147 AC XY: 6 AN XY: 40772

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

African (AFR) AF: 0.000184 AC: 4 AN: 21726

American (AMR) AF: 0.000126 AC: 1 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: 0.000488 AC: 2 AN: 4100

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

European-Non Finnish (NFE) AF: 0.000189 AC: 8 AN: 42370

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 = 0.000000050281), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;