14-23321471-T-TGGC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• 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 Uncertain_significance. Variant got 3 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-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}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PABPN1	NM_004643.4	c.21_23dup	p.Ala10dup	inframe_insertion	1/7	ENST00000216727.9
BCL2L2-PABPN1	NM_001387343.1	c.529-691_529-689dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PABPN1	ENST00000216727.9	c.21_23dup	p.Ala10dup	inframe_insertion	1/7	1	NM_004643.4	P1
PABPN1	ENST00000397276.6	c.21_23dup	p.Ala10dup	inframe_insertion	1/6	1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 213 AN: 150644 Hom.: 1 Cov.: 32

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

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

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

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:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Oculopharyngeal muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 08, 2023

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 03, 2022

Variant summary: PABPN1 c.21_23dupGGC (p.Ala11dup, also known as (GCG)7) 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 0.0014 in 150644 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.21_23dupGGC has been reported in the literature in individuals affected with Oculopharyngeal muscular dystrophy (Robinson_2005) or Rolandic epilepsy exercise-induced dystonia phenotype (Luthy_2019), though the allele did not co-segregate with disease. 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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;