NM_004643.4:c.21_23dupGGC

Variant names:

• chr14-23321471-T-TGGC
• rs193922941
• NM_004643.4:c.21_23dupGGC

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP5 BS1_Supporting BS2

The NM_004643.4(PABPN1):​c.21_23dupGGC​(p.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 0.00185 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 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 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: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]

ACMG classification

Verdict is Likely_benign. Variant got -2 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-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=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00141 (213/150754) while in subpopulation AMR AF= 0.00257 (39/15172). AF 95% confidence interval is 0.00193. There are 1 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1	NM_004643.4	c.21_23dupGGC	p.Ala8dup	disruptive_inframe_insertion	Exon 1 of 7	ENST00000216727.9	NP_004634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABPN1	ENST00000216727.9	c.21_23dupGGC	p.Ala8dup	disruptive_inframe_insertion	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4
BCL2L2-PABPN1	ENST00000678502.1	c.529-691_529-689dupGGC		intron_variant	Intron 4 of 9			ENSP00000503309.1

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:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Aug 21, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 9462747) -

Oculopharyngeal muscular dystrophy Pathogenic:1

Aug 08, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jun 20, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PABPN1 c.21_23dupGGC (p.Ala11dup) 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 0.0018 in 1155712 control chromosomes in the gnomAD database, including 3 homozygotes (gnomAD v4). The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in PABPN1 causing Oculopharyngeal Muscular Dystrophy phenotype. However, the variant is located in a microsatellite region and it is unknown how this may affect the accuracy of this data. c.21_23dupGGC has been reported in the literature in individuals affected with Oculopharyngeal muscular dystrophy (e.g. Robinson_2005) or Rolandic epilepsy exercise-induced dystonia (e.g. Luthy_2019), though the allele did not co-segregate with disease in either study. 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. The following publications have been ascertained in the context of this evaluation (PMID: 31257402, 15645184). ClinVar contains an entry for this variant (Variation ID: 1323407). 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;