chr2-60782678-TAA-T

Variant names:

• chr2-60782678-TAA-T
• rs1449808552
• NM_022894.4:c.1028-7_1028-6delAA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_022894.4(PAPOLG):​c.1028-7_1028-6delAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,256,392 control chromosomes in the GnomAD database, including 2 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0017 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAPOLG NM_022894.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.400
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 2-60782678-TAA-T is Benign according to our data. Variant chr2-60782678-TAA-T is described in ClinVar as Benign. ClinVar VariationId is 781680.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

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.1028-7_1028-6delAA		splice_region 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.1028-7_1028-6delAA		splice_region intron	N/A	ENSP00000238714.3	Q9BWT3-1
	PAPOLG	ENST00000412217.1	TSL:1	c.32-7_32-6delAA		splice_region intron	N/A	ENSP00000405570.1	A0A0C4DH56
	PAPOLG	ENST00000414060.5	TSL:1	n.*118-7_*118-6delAA		splice_region intron	N/A	ENSP00000405599.1	F8WAT4

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 1799 AN: 124860 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0227

Gnomad AMR AF: 0.00646

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00736

Gnomad SAS AF: 0.00630

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00394

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0176

GnomAD2 exomes AF: 0.00110 AC: 142 AN: 129158 AF XY: 0.00120

Gnomad AFR exome AF: 0.000733

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.00264

Gnomad FIN exome AF: 0.00150

Gnomad NFE exome AF: 0.000675

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.00169 AC: 2122 AN: 1256392 Hom.: 2 AF XY: 0.00189 AC XY: 1173 AN XY: 621950

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

African (AFR) AF: 0.00109 AC: 26 AN: 23758

American (AMR) AF: 0.00309 AC: 63 AN: 20376

Ashkenazi Jewish (ASJ) AF: 0.00342 AC: 62 AN: 18150

East Asian (EAS) AF: 0.00158 AC: 50 AN: 31552

South Asian (SAS) AF: 0.00659 AC: 420 AN: 63706

European-Finnish (FIN) AF: 0.00762 AC: 326 AN: 42786

Middle Eastern (MID) AF: 0.00234 AC: 9 AN: 3840

European-Non Finnish (NFE) AF: 0.00108 AC: 1082 AN: 1003312

Other (OTH) AF: 0.00172 AC: 84 AN: 48912

⚠️ 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: 0.0144 AC: 1799 AN: 124910 Hom.: 0 Cov.: 0 AF XY: 0.0137 AC XY: 822 AN XY: 60036

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

African (AFR) AF: 0.0140 AC: 452 AN: 32172

American (AMR) AF: 0.00645 AC: 80 AN: 12410

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 37 AN: 2972

East Asian (EAS) AF: 0.00738 AC: 36 AN: 4876

South Asian (SAS) AF: 0.00633 AC: 26 AN: 4106

European-Finnish (FIN) AF: 0.0156 AC: 99 AN: 6340

Middle Eastern (MID) AF: 0.00424 AC: 1 AN: 236

European-Non Finnish (NFE) AF: 0.0172 AC: 1020 AN: 59294

Other (OTH) AF: 0.0174 AC: 29 AN: 1668

⚠️ 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.

Alfa AF: 0.0531 Hom.: 1

ClinVar

ClinVar submissions

Significance: 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		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1449808552; hg19: chr2-61009813;