14-23321497-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_004643.4(PABPN1):c.28G>C(p.Ala10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,066,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000019 ( 0 hom. )

Consequence

PABPN1
NM_004643.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.80

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 3 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;

BP4

Computational evidence support a benign effect (MetaRNN=0.36351317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1	NM_004643.4 link	c.28G>C	p.Ala10Pro	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.28G>C	p.Ala10Pro	missense_variant	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4		Q86U42-1
BCL2L2-PABPN1	ENST00000678502.1 link	c.529-684G>C		intron_variant	Intron 4 of 9			ENSP00000503309.1		A0A7I2V383

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000188

AC:

AN:

1066120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

506610

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21864

American (AMR)

AF:

0.000133

AC:

AN:

7534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12902

East Asian (EAS)

AF:

0.00

AC:

AN:

24190

South Asian (SAS)

AF:

0.00

AC:

AN:

19602

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2802

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

910138

Other (OTH)

AF:

0.0000240

AC:

AN:

41740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 27, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.28G>C (p.A10P) alteration is located in exon 1 (coding exon 1) of the PABPN1 gene. This alteration results from a G to C substitution at nucleotide position 28, causing the alanine (A) at amino acid position 10 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.00041

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.088

T;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.52

T;T

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.34

N;N

PhyloP100

2.8

PROVEAN

Benign

0.11

N;N

REVEL

Benign

0.076

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.12

T;T

Polyphen

0.87

P;P

Vest4

0.34

MutPred

0.34

Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);

MVP

0.56

MPC

1.1

ClinPred

0.64

GERP RS

3.4

PromoterAI

-0.0038

Neutral

(source)

Varity_R

0.46

gMVP

0.46

Mutation Taster

=83/17

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over