14-23321471-T-TGGC

Position:

chr14-23321471-T-TGGC

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP5BS2

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 2.81

Variant links:

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]

PABPN1 links:

BCL2L2-PABPN1 (HGNC:):

BCL2L2-PABPN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 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-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}.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PABPN1	NM_004643.4 linkuse as main transcript	c.21_23dup	p.Ala10dup	inframe_insertion	1/7	ENST00000216727.9	NP_004634.1
BCL2L2-PABPN1	NM_001387343.1 linkuse as main transcript	c.529-691_529-689dup		intron_variant			NP_001374272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PABPN1	ENST00000216727.9 linkuse as main transcript	c.21_23dup	p.Ala10dup	inframe_insertion	1/7	1	NM_004643.4	ENSP00000216727	P1	Q86U42-1
PABPN1	ENST00000397276.6 linkuse as main transcript	c.21_23dup	p.Ala10dup	inframe_insertion	1/6	1		ENSP00000380446		Q86U42-2

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

213

AN:

150644

Hom.:

Cov.:

show subpopulations

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:

AN:

7496

Hom.:

AF XY:

0.000758

AC XY:

AN XY:

3956

show subpopulations

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.:

Cov.:

AF XY:

0.00196

AC XY:

933

AN XY:

476174

show subpopulations

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.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

73652

show subpopulations

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:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

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

Jun 20, 2024

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

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over