Variant chr14-23321471-T-TGGCGGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong

The ENST00000216727.9(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
ENST00000216727.9 inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a region_of_interest Disordered (size 114) in uniprot entity PABP2_HUMAN there are 29 pathogenic changes around while only 2 benign (94%) in ENST00000216727.9

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	Protein	UniProt
PABPN1	NM_004643.4 linkuse as main transcript	c.18_23dup	p.Ala10_Ala11dup	inframe_insertion	1/7	ENST00000216727.9	NP_004634.1
BCL2L2-PABPN1	NM_001387343.1 linkuse as main transcript	c.529-694_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.18_23dup	p.Ala10_Ala11dup	inframe_insertion	1/7	1	NM_004643.4	ENSP00000216727	P1	Q86U42-1
PABPN1	ENST00000397276.6 linkuse as main transcript	c.18_23dup	p.Ala10_Ala11dup	inframe_insertion	1/6	1		ENSP00000380446		Q86U42-2

Frequencies

GnomAD3 genomes

AF:

0.0000531

AC:

AN:

150644

Hom.:

Cov.:

show subpopulations

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:

AN:

1004976

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

476184

show subpopulations

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:

AN:

150644

Hom.:

Cov.:

AF XY:

0.0000680

AC XY:

AN XY:

73536

show subpopulations

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

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

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. -
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 -

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