14-23321504-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_004643.4(PABPN1):c.35G>C(p.Gly12Ala) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PABPN1 NM_004643.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.21

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 5 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
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-23321504-G-C is Pathogenic according to our data. Variant chr14-23321504-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7368.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr14-23321504-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PABPN1	NM_004643.4	c.35G>C	p.Gly12Ala	missense_variant	1/7	ENST00000216727.9
BCL2L2-PABPN1	NM_001387343.1	c.529-677G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PABPN1	ENST00000216727.9	c.35G>C	p.Gly12Ala	missense_variant	1/7	1	NM_004643.4	P1
PABPN1	ENST00000397276.6	c.35G>C	p.Gly12Ala	missense_variant	1/6	1
PABPN1	ENST00000556821.5			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.29e-7 AC: 1 AN: 1075904 Hom.: 0 Cov.: 31 AF XY: 0.00000195 AC XY: 1 AN XY: 511762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000236

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PABPN1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2023

The PABPN1 c.35G>C variant is predicted to result in the amino acid substitution p.Gly12Ala. This variant has been reported in multiple unrelated individuals with oculopharyngeal muscular dystrophy (OPMD) who had family histories that included additional affected individuals, although none were available for confirmatory DNA testing (Robinson et al. 2006. PubMed ID: 16648376; Robinson et al. 2011. PubMed ID: 21742497; Nishii et al. 2021. PubMed ID: 34225694). This variant results in the substitution of a glycine to an alanine at codon 12, producing a run of 13 alanine amino acids, which mimic the effect of the common expansion mutation (Robinson et al. 2006. PubMed ID: 16648376). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Oculopharyngeal muscular dystrophy 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2006

- -

Oculopharyngeal muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Benign	0.094	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.58	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	A;A;A;A
PROVEAN	Benign	-0.070	N;N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.092	B;B
Vest4		0.32
MutPred		0.73		Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);
MVP		0.97
MPC		0.94
ClinPred		0.48	T
GERP RS		3.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		4.5
Varity_R		0.38
gMVP		0.35

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: rs104894466; hg19: chr14-23790713;