14-23321490-G-GGCA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP5_Moderate

The NM_004643.4(PABPN1):c.30_32dup(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 0.000478 in 1,198,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: PABPN1 NM_004643.4 inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.57

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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 14-23321490-G-GGCA is Pathogenic according to our data. Variant chr14-23321490-G-GGCA is described in ClinVar as [Pathogenic]. Clinvar id is 1323406.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PABPN1	NM_004643.4	c.30_32dup	p.Ala10dup	inframe_insertion	1/7	ENST00000216727.9
BCL2L2-PABPN1	NM_001387343.1	c.529-682_529-680dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PABPN1	ENST00000216727.9	c.30_32dup	p.Ala10dup	inframe_insertion	1/7	1	NM_004643.4	P1
PABPN1	ENST00000397276.6	c.30_32dup	p.Ala10dup	inframe_insertion	1/6	1

Frequencies

GnomAD3 genomes AF: 0.000332 AC: 50 AN: 150828 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000285 AC: 2 AN: 7014 Hom.: 0 AF XY: 0.000540 AC XY: 2 AN XY: 3706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad SAS 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.: 0 Cov.: 31 AF XY: 0.000519 AC XY: 258 AN XY: 497094

Gnomad4 AFR exome AF: 0.0000468

Gnomad4 AMR exome AF: 0.000711

Gnomad4 ASJ exome AF: 0.000243

Gnomad4 EAS exome AF: 0.00115

Gnomad4 SAS exome AF: 0.000103

Gnomad4 FIN exome AF: 0.0000430

Gnomad4 NFE exome AF: 0.000523

Gnomad4 OTH exome AF: 0.000370

GnomAD4 genome AF: 0.000331 AC: 50 AN: 150936 Hom.: 0 Cov.: 32 AF XY: 0.000312 AC XY: 23 AN XY: 73758

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000592

Gnomad4 OTH AF: 0.00

Asia WGS AF: 0.000582 AC: 2 AN: 3452

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oculopharyngeal muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 18, 2024

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1401656265; hg19: chr14-23790699;