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. Variant got 2 ACMG points: 4P and 2B. PVS1_Moderate PM2 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. 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

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 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 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.
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 710413.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 15 AN: 85786 Hom.: 0 Cov.: 24 FAILED QC

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

Gnomad4 AFR AF: 0.000184

Gnomad4 AMR AF: 0.000126

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000488

Gnomad4 NFE AF: 0.000189

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 18, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553378906; hg19: chr2-61009815;