14-23321471-TGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGC

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong

The NM_004643.4(PABPN1):c.15_23dupGGCGGCGGC(p.Ala6_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 0.0000164 in 1,155,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PABPN1
NM_004643.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

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]

PABPN1 links:

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]

BCL2L2-PABPN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a region_of_interest Interaction with SKIP (size 143) in uniprot entity PABP2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_004643.4

PP5

Variant 14-23321471-T-TGGCGGCGGC is Pathogenic according to our data. Variant chr14-23321471-T-TGGCGGCGGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1	NM_004643.4 link	c.15_23dupGGCGGCGGC	p.Ala6_Ala8dup	disruptive_inframe_insertion	Exon 1 of 7	ENST00000216727.9	NP_004634.1	Q86U42-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABPN1	ENST00000216727.9 link	c.15_23dupGGCGGCGGC	p.Ala6_Ala8dup	disruptive_inframe_insertion	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4		Q86U42-1
BCL2L2-PABPN1	ENST00000678502.1 link	c.529-697_529-689dupGGCGGCGGC		intron_variant	Intron 4 of 9			ENSP00000503309.1		A0A7I2V383

Frequencies

GnomAD3 genomes

AF:

0.0000531

AC:

AN:

150644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000740

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1004976

Hom.:

Cov.:

AF XY:

0.0000147

AC XY:

AN XY:

476184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000501

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000114

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000531

AC:

AN:

150754

Hom.:

Cov.:

AF XY:

0.0000815

AC XY:

AN XY:

73652

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000741

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Dec 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.15_23dupGGCGGCGGC variant in the PABPN1 gene has been reported previously in multiple individuals with oculopharyngeal muscular dystrophy (OPMD), and accounts for up to 40% of pathogenic PABPN1 expansion alleles (Brais et al., 1998; Trollet et al., 2014). The c.15_23dupGGCGGCGGC causes an in-frame duplication of 3 Alanine repeats expanding the normal tract of 10 Alanines to a pathogenic repeat expansion of 13 Alanines, denoted p.A9_A11dup. Sufficient data from control individuals in the NHLBI Exome Sequencing Project and Exome Aggregation Consortium data sets were not available to assess the frequency of the c.15_23dupGGCGGCGGC variant in the general population. We interpret c.15_23dupGGCGGCGGC as a pathogenic variant. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 27, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oculopharyngeal muscular dystrophy

Pathogenic:4

Mar 12, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 08, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Feb 23, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.15_23dupGGCGGCGGC (p.A9_A11dup) alteration, located in coding exon 1 of the PABPN1 gene, results from an in-frame duplication of 9 nucleotides at positions 15 to 23. This results in the insertion of 3 alanine residues between codons 9 and 11. This is a GCN trinucleotide repeat expansion with 13 repeats; also known as GCN[13]. Based on data from gnomAD, this allele has an overall frequency of 0.003% (1/29646) total alleles studied. The highest observed frequency was 0.007% (1/14964) of European (non-Finnish) alleles. Most individuals with oculopharyngeal muscular dystrophy carry a heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of the PABPN1 gene (Trollet, 2020) This amino acid position is well conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic. -

Oculopharyngeal muscular dystrophy 1

Pathogenic:1

Aug 22, 2023

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over