14-23321484-G-GGCGGCGGCA

Position:

• chr14-23321484-G-GGCGGCGGCA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The ENST00000216727.9(PABPN1):​c.18_26dup​(p.Ala9_Ala11dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PABPN1 ENST00000216727.9 inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.97

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 Pathogenic. Variant got 12 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
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-23321484-G-GGCGGCGGCA is Pathogenic according to our data. Variant chr14-23321484-G-GGCGGCGGCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 987098.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	c.18_26dup	p.Ala9_Ala11dup	inframe_insertion	1/7	ENST00000216727.9	NP_004634.1
BCL2L2-PABPN1	NM_001387343.1	c.529-694_529-686dup		intron_variant			NP_001374272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PABPN1	ENST00000216727.9	c.18_26dup	p.Ala9_Ala11dup	inframe_insertion	1/7	1	NM_004643.4	ENSP00000216727	P1
PABPN1	ENST00000397276.6	c.18_26dup	p.Ala9_Ala11dup	inframe_insertion	1/6	1		ENSP00000380446

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Oculopharyngeal muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 08, 2023

- -

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: rs1888252890; hg19: chr14-23790693;