14-23321471-T-TGGCGGCGGCGGC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_004643.4(PABPN1):c.12_23dup(p.Ala8_Ala11dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000664 in 150,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PABPN1 NM_004643.4 inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 12 ACMG points.

• PM1: In a region_of_interest Disordered (size 114) in uniprot entity PABP2_HUMAN there are 30 pathogenic changes around while only 2 benign (94%) in NM_004643.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-23321471-T-TGGCGGCGGCGGC is Pathogenic according to our data. Variant chr14-23321471-T-TGGCGGCGGCGGC is described in ClinVar as [Pathogenic]. Clinvar id is 503634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PABPN1	NM_004643.4	c.12_23dup	p.Ala8_Ala11dup	inframe_insertion	1/7	ENST00000216727.9
BCL2L2-PABPN1	NM_001387343.1	c.529-700_529-689dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PABPN1	ENST00000216727.9	c.12_23dup	p.Ala8_Ala11dup	inframe_insertion	1/7	1	NM_004643.4	P1
PABPN1	ENST00000397276.6	c.12_23dup	p.Ala8_Ala11dup	inframe_insertion	1/6	1

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150644 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.95e-7 AC: 1 AN: 1004976 Hom.: 0 Cov.: 31 AF XY: 0.00000210 AC XY: 1 AN XY: 476184

Gnomad4 AFR exome AF: 0.00

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: 0.00000114

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150644 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73536

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oculopharyngeal muscular dystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 08, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2018

This individual harbors one expanded allele of 14 Alanine repeats and one normal allele of 10 Alanine repeats. This repeat expansion in the PABPN1 gene has been reported previously in multiple individuals with oculopharyngeal muscular dystrophy (OPMD) (Brais et al., 1998; Robinson et al., 2005). The finding of an expanded allele in the PABPN1 gene is consistent with a diagnosis of oculopharyngeal muscular dystrophy. -

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;