chr14-23321471-T-TGGC

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP5BS2

The NM_004643.4(PABPN1):​c.21_23dup​(p.Ala10dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,155,712 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0019 ( 2 hom. )

Consequence

PABPN1
NM_004643.4 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 2.81
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1
In a region_of_interest Disordered (size 114) in uniprot entity PABP2_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_004643.4
PP5
Variant 14-23321471-T-TGGC is Pathogenic according to our data. Variant chr14-23321471-T-TGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1323407.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PABPN1NM_004643.4 linkuse as main transcriptc.21_23dup p.Ala10dup inframe_insertion 1/7 ENST00000216727.9 NP_004634.1
BCL2L2-PABPN1NM_001387343.1 linkuse as main transcriptc.529-691_529-689dup intron_variant NP_001374272.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PABPN1ENST00000216727.9 linkuse as main transcriptc.21_23dup p.Ala10dup inframe_insertion 1/71 NM_004643.4 ENSP00000216727 P1Q86U42-1
PABPN1ENST00000397276.6 linkuse as main transcriptc.21_23dup p.Ala10dup inframe_insertion 1/61 ENSP00000380446 Q86U42-2

Frequencies

GnomAD3 genomes
AF:
0.00141
AC:
213
AN:
150644
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000461
Gnomad AMI
AF:
0.00879
Gnomad AMR
AF:
0.00257
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.00207
Gnomad OTH
AF:
0.00289
GnomAD3 exomes
AF:
0.000934
AC:
7
AN:
7496
Hom.:
0
AF XY:
0.000758
AC XY:
3
AN XY:
3956
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00137
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00191
AC:
1921
AN:
1004958
Hom.:
2
Cov.:
31
AF XY:
0.00196
AC XY:
933
AN XY:
476174
show subpopulations
Gnomad4 AFR exome
AF:
0.000300
Gnomad4 AMR exome
AF:
0.00242
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000339
Gnomad4 SAS exome
AF:
0.000528
Gnomad4 FIN exome
AF:
0.000110
Gnomad4 NFE exome
AF:
0.00207
Gnomad4 OTH exome
AF:
0.00180
GnomAD4 genome
AF:
0.00141
AC:
213
AN:
150754
Hom.:
1
Cov.:
32
AF XY:
0.00113
AC XY:
83
AN XY:
73652
show subpopulations
Gnomad4 AFR
AF:
0.000460
Gnomad4 AMR
AF:
0.00257
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00207
Gnomad4 OTH
AF:
0.00286
Bravo
AF:
0.00162

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Oculopharyngeal muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityAug 08, 2023- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 20, 2024Variant summary: PABPN1 c.21_23dupGGC (p.Ala11dup) results in an in-frame duplication that is predicted to duplicate one amino acid into the encoded protein. The variant allele was found at a frequency of 0.0018 in 1155712 control chromosomes in the gnomAD database, including 3 homozygotes (gnomAD v4). The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in PABPN1 causing Oculopharyngeal Muscular Dystrophy phenotype. However, the variant is located in a microsatellite region and it is unknown how this may affect the accuracy of this data. c.21_23dupGGC has been reported in the literature in individuals affected with Oculopharyngeal muscular dystrophy (e.g. Robinson_2005) or Rolandic epilepsy exercise-induced dystonia (e.g. Luthy_2019), though the allele did not co-segregate with disease in either study. These reports do not provide unequivocal conclusions about association of the variant with Oculopharyngeal Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31257402, 15645184). ClinVar contains an entry for this variant (Variation ID: 1323407). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs193922941; hg19: chr14-23790680; API