NM_004643.4:c.21_26dupGGCAGC

Variant names:

• chr14-23321487-G-GGCGGCA
• rs1337792814
• NM_004643.4:c.21_26dupGGCAGC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PP5_Moderate BS2_Supporting

The NM_004643.4(PABPN1):​c.21_26dupGGCAGC​(p.Ala8_Ala9dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00000754 in 1,194,274 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: PABPN1 NM_004643.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.39

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a region_of_interest Disordered (size 114) in uniprot entity PABP2_HUMAN there are 30 pathogenic changes around while only 2 benign (94%) in NM_004643.4
• PP5: Variant 14-23321487-G-GGCGGCA is Pathogenic according to our data. Variant chr14-23321487-G-GGCGGCA is described in ClinVar as [Pathogenic]. Clinvar id is 2437738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 5 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	c.21_26dupGGCAGC	p.Ala8_Ala9dup	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_26dupGGCAGC	p.Ala8_Ala9dup	disruptive_inframe_insertion	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4
BCL2L2-PABPN1	ENST00000678502.1	c.529-691_529-686dupGGCAGC		intron_variant	Intron 4 of 9			ENSP00000503309.1

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 5 AN: 150908 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000383 AC: 4 AN: 1043366 Hom.: 0 Cov.: 31 AF XY: 0.00000404 AC XY: 2 AN XY: 495144

African (AFR) AF: 0.00 AC: 0 AN: 21184

American (AMR) AF: 0.00 AC: 0 AN: 6840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12112

East Asian (EAS) AF: 0.00 AC: 0 AN: 22076

South Asian (SAS) AF: 0.00 AC: 0 AN: 19322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2720

European-Non Finnish (NFE) AF: 0.00000446 AC: 4 AN: 896482

Other (OTH) AF: 0.00 AC: 0 AN: 40234

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 150908 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73672

African (AFR) AF: 0.00 AC: 0 AN: 41294

American (AMR) AF: 0.000198 AC: 3 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67644

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.0000660 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oculopharyngeal muscular dystrophy Pathogenic:1

Aug 08, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=76/24	polymorphism

Splicing

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

Publications

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Other links and lift over

dbSNP: rs1337792814; hg19: chr14-23790696;