NM_004643.4:c.18_23dupGGCGGC

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_StrongBP3BS2_Supporting

The NM_004643.4(PABPN1):c.18_23dupGGCGGC(p.Ala7_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 0.000032 in 1,155,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A8A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PABPN1
NM_004643.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 2.81

Publications

1 publications found

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: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]

BCL2L2-PABPN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PP5

Variant 14-23321471-T-TGGCGGC is Pathogenic according to our data. Variant chr14-23321471-T-TGGCGGC is described in ClinVar as Pathogenic. ClinVar VariationId is 280233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP3

Nonframeshift variant in repetitive region in NM_004643.4

BS2

High AC in GnomAd4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004643.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PABPN1	NM_004643.4	MANE Select	c.18_23dupGGCGGC	p.Ala7_Ala8dup	disruptive_inframe_insertion	Exon 1 of 7	NP_004634.1
PABPN1	NM_001360551.3		c.18_23dupGGCGGC	p.Ala7_Ala8dup	disruptive_inframe_insertion	Exon 1 of 6	NP_001347480.1
BCL2L2-PABPN1	NM_001387340.1		c.550-694_550-689dupGGCGGC		intron	N/A	NP_001374269.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PABPN1	ENST00000216727.9	TSL:1 MANE Select	c.18_23dupGGCGGC	p.Ala7_Ala8dup	disruptive_inframe_insertion	Exon 1 of 7	ENSP00000216727.4
PABPN1	ENST00000397276.6	TSL:1	c.18_23dupGGCGGC	p.Ala7_Ala8dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000380446.2
BCL2L2-PABPN1	ENST00000553781.5	TSL:2	c.433-694_433-689dupGGCGGC		intron	N/A	ENSP00000451320.1

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

African (AFR)

AF:

0.0000501

AC:

AN:

19974

American (AMR)

AF:

0.00

AC:

AN:

5794

Ashkenazi Jewish (ASJ)

AF:

0.0000942

AC:

AN:

10612

East Asian (EAS)

AF:

0.00

AC:

AN:

17698

South Asian (SAS)

AF:

0.0000528

AC:

AN:

18946

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2592

European-Non Finnish (NFE)

AF:

0.0000286

AC:

AN:

873488

Other (OTH)

AF:

0.0000265

AC:

AN:

37754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000531

AC:

AN:

150644

Hom.:

Cov.:

AF XY:

0.0000680

AC XY:

AN XY:

73536

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41178

American (AMR)

AF:

0.00

AC:

AN:

15150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67522

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PABPN1: PM1:Strong, PM2, PP1:Moderate, PP4:Moderate, PS4:Moderate

May 24, 2018

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

Mutation Taster

=23/177

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over