14-23321495-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4 BP6

The NM_004643.4(PABPN1):c.26C>T(p.Ala9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000495 in 1,212,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: PABPN1 NM_004643.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.78

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 0 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.38109824).
• BP6: Variant 14-23321495-C-T is Benign according to our data. Variant chr14-23321495-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2434543.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PABPN1	NM_004643.4	c.26C>T	p.Ala9Val	missense_variant	1/7	ENST00000216727.9
BCL2L2-PABPN1	NM_001387343.1	c.529-686C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PABPN1	ENST00000216727.9	c.26C>T	p.Ala9Val	missense_variant	1/7	1	NM_004643.4	P1
PABPN1	ENST00000397276.6	c.26C>T	p.Ala9Val	missense_variant	1/6	1
PABPN1	ENST00000556821.5			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150932 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000471 AC: 5 AN: 1061850 Hom.: 0 Cov.: 31 AF XY: 0.00000793 AC XY: 4 AN XY: 504358

Gnomad4 AFR exome AF: 0.0000460

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: 0.00000441

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150932 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73704

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Oculopharyngeal muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 15, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

PABPN1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.0074	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.095	T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.59	T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.98	D;D
Vest4		0.33
MutPred		0.42		Gain of catalytic residue at A9 (P = 0.045);Gain of catalytic residue at A9 (P = 0.045);
MVP		0.54
MPC		0.87
ClinPred		0.70	D
GERP RS		3.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		4.4
Varity_R		0.30
gMVP		0.25

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: rs1433496791; hg19: chr14-23790704;