14-23321471-TGGC-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PS1_Moderate

The NM_004643.4(PABPN1):c.21_23del(p.Ala11?) variant causes a start lost, inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,152,136 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (0 hom.)
• Consequence: PABPN1 NM_004643.4 start_lost, inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81

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 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_004643.4 (PABPN1) was described as [Pathogenic] in Lovd

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PABPN1	NM_004643.4	c.21_23del	p.Ala11?	start_lost, inframe_deletion	1/7	ENST00000216727.9
BCL2L2-PABPN1	NM_001387343.1	c.529-691_529-689del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PABPN1	ENST00000216727.9	c.21_23del	p.Ala11?	start_lost, inframe_deletion	1/7	1	NM_004643.4	P1
PABPN1	ENST00000397276.6	c.21_23del	p.Ala11?	start_lost, inframe_deletion	1/6	1

Frequencies

GnomAD3 genomes AF: 0.000259 AC: 39 AN: 150628 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000486

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: 0.00318

Gnomad NFE AF: 0.000489

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00120 AC: 9 AN: 7496 Hom.: 0 AF XY: 0.00126 AC XY: 5 AN XY: 3956

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.000781

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000710 AC: 711 AN: 1001398 Hom.: 0 AF XY: 0.000738 AC XY: 350 AN XY: 474352

Gnomad4 AFR exome AF: 0.000553

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.000475

Gnomad4 EAS exome AF: 0.00229

Gnomad4 SAS exome AF: 0.000212

Gnomad4 FIN exome AF: 0.00213

Gnomad4 NFE exome AF: 0.000652

Gnomad4 OTH exome AF: 0.000932

GnomAD4 genome AF: 0.000259 AC: 39 AN: 150738 Hom.: 1 Cov.: 32 AF XY: 0.000149 AC XY: 11 AN XY: 73640

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000489

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oculopharyngeal muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922941; hg19: chr14-23790680;