14-23321471-TGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGC
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_StrongBP3
The NM_004643.4(PABPN1):c.12_23dupGGCGGCGGCGGC(p.Ala5_Ala8dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000664 in 150,644 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. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A8A) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000010 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PABPN1
NM_004643.4 disruptive_inframe_insertion
NM_004643.4 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.81
Publications
1 publications found
Genes affected
PABPN1 (HGNC:8565): (poly(A) binding protein nuclear 1) This gene encodes an abundant nuclear protein that binds with high affinity to nascent poly(A) tails. The protein is required for progressive and efficient polymerization of poly(A) tails at the 3' ends of eukaryotic transcripts and controls the size of the poly(A) tail to about 250 nt. At steady-state, this protein is localized in the nucleus whereas a different poly(A) binding protein is localized in the cytoplasm. This gene contains a GCG trinucleotide repeat at the 5' end of the coding region, and expansion of this repeat from the normal 6 copies to 8-13 copies leads to autosomal dominant oculopharyngeal muscular dystrophy (OPMD) disease. Related pseudogenes have been identified on chromosomes 19 and X. Read-through transcription also exists between this gene and the neighboring upstream BCL2-like 2 (BCL2L2) gene. [provided by RefSeq, Dec 2010]
BCL2L2-PABPN1 (HGNC:42959): (BCL2L2-PABPN1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring BCL2L2 (BCL2-like 2) and PABPN1 (poly(A) binding protein, nuclear 1) genes on chromosome 14. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Dec 2010]
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
PP5
Variant 14-23321471-T-TGGCGGCGGCGGC is Pathogenic according to our data. Variant chr14-23321471-T-TGGCGGCGGCGGC is described in ClinVar as Pathogenic. ClinVar VariationId is 503634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP3
Nonframeshift variant in repetitive region in NM_004643.4
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_004643.4. 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 |
|---|---|---|---|---|---|---|---|---|---|
| PABPN1 | MANE Select | c.12_23dupGGCGGCGGCGGC | p.Ala5_Ala8dup | disruptive_inframe_insertion | Exon 1 of 7 | NP_004634.1 | Q86U42-1 | ||
| PABPN1 | c.12_23dupGGCGGCGGCGGC | p.Ala5_Ala8dup | disruptive_inframe_insertion | Exon 1 of 6 | NP_001347480.1 | Q86U42-2 | |||
| BCL2L2-PABPN1 | c.550-700_550-689dupGGCGGCGGCGGC | intron | N/A | NP_001374269.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PABPN1 | TSL:1 MANE Select | c.12_23dupGGCGGCGGCGGC | p.Ala5_Ala8dup | disruptive_inframe_insertion | Exon 1 of 7 | ENSP00000216727.4 | Q86U42-1 | ||
| PABPN1 | TSL:1 | c.12_23dupGGCGGCGGCGGC | p.Ala5_Ala8dup | disruptive_inframe_insertion | Exon 1 of 6 | ENSP00000380446.2 | Q86U42-2 | ||
| BCL2L2-PABPN1 | TSL:2 | c.433-700_433-689dupGGCGGCGGCGGC | intron | N/A | ENSP00000451320.1 | Q92843-2 |
Frequencies
GnomAD3 genomes 0.00000664 AC: 1AN: 150644Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
150644
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.95e-7 AC: 1AN: 1004976Hom.: 0 Cov.: 31 AF XY: 0.00000210 AC XY: 1AN XY: 476184 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1004976
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
476184
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
19974
American (AMR)
AF:
AC:
0
AN:
5794
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
10612
East Asian (EAS)
AF:
AC:
0
AN:
17698
South Asian (SAS)
AF:
AC:
0
AN:
18946
European-Finnish (FIN)
AF:
AC:
0
AN:
18118
Middle Eastern (MID)
AF:
AC:
0
AN:
2592
European-Non Finnish (NFE)
AF:
AC:
1
AN:
873488
Other (OTH)
AF:
AC:
0
AN:
37754
⚠️ 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.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
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4
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<30
30-35
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>80
Age
GnomAD4 genome 0.00000664 AC: 1AN: 150644Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73536 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
150644
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
73536
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41178
American (AMR)
AF:
AC:
0
AN:
15150
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3456
East Asian (EAS)
AF:
AC:
0
AN:
5138
South Asian (SAS)
AF:
AC:
0
AN:
4790
European-Finnish (FIN)
AF:
AC:
0
AN:
10110
Middle Eastern (MID)
AF:
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
AC:
1
AN:
67522
Other (OTH)
AF:
AC:
0
AN:
2076
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
2
-
-
Oculopharyngeal muscular dystrophy (2)
2
-
-
Oculopharyngeal muscular dystrophy 1 (2)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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