14-23321471-T-TGGCGGC

Variant summary

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

The NM_004643.4(PABPN1):c.18_23dup(p.Ala10_Ala11dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000032 in 1,155,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: PABPN1 NM_004643.4 inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 30 pathogenic changes around while only 2 benign (94%) in NM_004643.4
• PP5: Variant 14-23321471-T-TGGCGGC is Pathogenic according to our data. Variant chr14-23321471-T-TGGCGGC is described in ClinVar as [Pathogenic]. Clinvar id is 280233.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.18_23dup	p.Ala10_Ala11dup	inframe_insertion	1/7	ENST00000216727.9
BCL2L2-PABPN1	NM_001387343.1	c.529-694_529-689dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PABPN1	ENST00000216727.9	c.18_23dup	p.Ala10_Ala11dup	inframe_insertion	1/7	1	NM_004643.4	P1
PABPN1	ENST00000397276.6	c.18_23dup	p.Ala10_Ala11dup	inframe_insertion	1/6	1

Frequencies

GnomAD3 genomes AF: 0.0000531 AC: 8 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: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000289 AC: 29 AN: 1004976 Hom.: 0 Cov.: 31 AF XY: 0.0000273 AC XY: 13 AN XY: 476184

Gnomad4 AFR exome AF: 0.0000501

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000942

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000528

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000286

Gnomad4 OTH exome AF: 0.0000265

GnomAD4 genome AF: 0.0000531 AC: 8 AN: 150644 Hom.: 0 Cov.: 32 AF XY: 0.0000680 AC XY: 5 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: 0.000118

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	PABPN1: PM1:Strong, PM2, PP1:Moderate, PP4:Moderate, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2018	The c.18_23dupGGCGGC pathogenic variant in the PABPN1 gene has been reported previously in individuals with oculopharyngeal muscular dystrophy in four families (Brais et al., 1998). This duplication is in the region of the polyalanine tract in exon 1, and other duplications nearby have been reported in the Human Gene Mutation Database in association with oculopharyngeal muscular dystrophy (Stenson et al., 2014). The c.18_23dupGGCGGC variant causes an in-frame duplication of 2 alanine residues, denoted p.Ala10_Ala11dup. The result of this variant is a polyalanine tract length of 12 in this individual. The c.18_23dupGGCGGC variant was not observed in approximately 192 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.18_23dupGGCGGC as a pathogenic variant. -

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;