chr14-23321504-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.3e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PABPN1
NM_004643.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 2.21

Publications

8 publications found

Variant links:

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]

PABPN1 links:

BCL2L2-PABPN1 (HGNC:42959): (BCL2L2-PABPN1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring BCL2L2 (BCL2-like 2) and PABPN1 (poly(A) binding protein, nuclear 1) genes on chromosome 14. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Dec 2010]

BCL2L2-PABPN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1	NM_004643.4 link	c.35G>C	p.Gly12Ala	missense_variant	Exon 1 of 7	ENST00000216727.9	NP_004634.1	Q86U42-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABPN1	ENST00000216727.9 link	c.35G>C	p.Gly12Ala	missense_variant	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4		Q86U42-1
BCL2L2-PABPN1	ENST00000553781.5 link	c.433-677G>C		intron_variant	Intron 3 of 8	2		ENSP00000451320.1		Q92843-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.29e-7

AC:

AN:

1075904

Hom.:

Cov.:

AF XY:

0.00000195

AC XY:

AN XY:

511762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22150

American (AMR)

AF:

0.00

AC:

AN:

7790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13294

East Asian (EAS)

AF:

0.00

AC:

AN:

25074

South Asian (SAS)

AF:

0.00

AC:

AN:

19814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2848

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

915508

Other (OTH)

AF:

0.0000236

AC:

AN:

42312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PABPN1-related disorder

Pathogenic:1

Dec 18, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

May 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oculopharyngeal muscular dystrophy

Uncertain:1

Jul 22, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.094

T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.027

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.58

T;T

M_CAP

Pathogenic

0.95

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.34

N;N

PhyloP100

2.2

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

GERP RS

3.4

PromoterAI

0.046

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

4.5

Varity_R

0.38

gMVP

0.35

Mutation Taster

=28/72

disease causing (ClinVar)

(source)

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

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chr14-23321504-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over