14-23321471-T-TGGCGGCGGC

Position:

• chr14-23321471-T-TGGCGGCGGC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

The NM_004643.4(PABPN1):​c.15_23dup​(p.Ala9_Ala11dup) variant causes a 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 inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.81

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:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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-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/exons	MANE	Protein	UniProt
PABPN1	NM_004643.4	c.15_23dup	p.Ala9_Ala11dup	inframe_insertion	1/7	ENST00000216727.9	NP_004634.1
BCL2L2-PABPN1	NM_001387343.1	c.529-697_529-689dup		intron_variant			NP_001374272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PABPN1	ENST00000216727.9	c.15_23dup	p.Ala9_Ala11dup	inframe_insertion	1/7	1	NM_004643.4	ENSP00000216727	P1
PABPN1	ENST00000397276.6	c.15_23dup	p.Ala9_Ala11dup	inframe_insertion	1/6	1		ENSP00000380446

Frequencies

GnomAD3 genomes AF: 0.0000531 AC: 8 AN: 150644 Hom.: 0 Cov.: 32

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: 11 AN: 1004976 Hom.: 0 Cov.: 31 AF XY: 0.0000147 AC XY: 7 AN XY: 476184

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: 8 AN: 150754 Hom.: 0 Cov.: 32 AF XY: 0.0000815 AC XY: 6 AN XY: 73652

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

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -

Oculopharyngeal muscular dystrophy Pathogenic:4

Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 12, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Aug 22, 2023

- -

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: rs193922941; hg19: chr14-23790680;