NM_004643.4:c.30_32dupAGC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5BS1_SupportingBS2_Supporting

The NM_004643.4(PABPN1):c.30_32dupAGC(p.Ala11dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,198,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

PABPN1
NM_004643.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.57

Publications

0 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_benign. The variant received -1 ACMG points.

PP5

Variant 14-23321490-G-GGCA is Pathogenic according to our data. Variant chr14-23321490-G-GGCA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1323406.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000499 (523/1047284) while in subpopulation EAS AF = 0.00115 (26/22638). AF 95% confidence interval is 0.000805. There are 0 homozygotes in GnomAdExome4. There are 258 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 50 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1	NM_004643.4 link	c.30_32dupAGC	p.Ala11dup	disruptive_inframe_insertion	Exon 1 of 7	ENST00000216727.9	NP_004634.1	Q86U42-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABPN1	ENST00000216727.9 link	c.30_32dupAGC	p.Ala11dup	disruptive_inframe_insertion	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4		Q86U42-1
BCL2L2-PABPN1	ENST00000553781.5 link	c.433-682_433-680dupAGC		intron_variant	Intron 3 of 8	2		ENSP00000451320.1		Q92843-2

Frequencies

GnomAD3 genomes

AF:

0.000332

AC:

AN:

150828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000727

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000592

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000285

AC:

AN:

7014

AF XY:

0.000540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000499

AC:

523

AN:

1047284

Hom.:

Cov.:

AF XY:

0.000519

AC XY:

258

AN XY:

497094

show subpopulations

African (AFR)

AF:

0.0000468

AC:

AN:

21354

American (AMR)

AF:

0.000711

AC:

AN:

7034

Ashkenazi Jewish (ASJ)

AF:

0.000243

AC:

AN:

12336

East Asian (EAS)

AF:

0.00115

AC:

AN:

22638

South Asian (SAS)

AF:

0.000103

AC:

AN:

19364

European-Finnish (FIN)

AF:

0.0000430

AC:

AN:

23230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2728

European-Non Finnish (NFE)

AF:

0.000523

AC:

470

AN:

898012

Other (OTH)

AF:

0.000370

AC:

AN:

40588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000331

AC:

AN:

150936

Hom.:

Cov.:

AF XY:

0.000312

AC XY:

AN XY:

73758

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41392

American (AMR)

AF:

0.000198

AC:

AN:

15156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000775

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000592

AC:

AN:

67598

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000108

Hom.:

Asia WGS

AF:

0.000582

AC:

AN:

3452

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

Jan 18, 2024

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oculopharyngeal muscular dystrophy 1

Uncertain:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM4+PS4_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=77/23

polymorphism

(source)

Splicing

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

Publications

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NM_004643.4:c.30_32dupAGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over