14-23321507-C-A

Position:

chr14-23321507-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The ENST00000216727.9(PABPN1):c.38C>A(p.Ala13Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 1,230,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 9.3e-7 ( 0 hom. )

Consequence

PABPN1
ENST00000216727.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41

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:):

BCL2L2-PABPN1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a region_of_interest Disordered (size 114) in uniprot entity PABP2_HUMAN there are 29 pathogenic changes around while only 2 benign (94%) in ENST00000216727.9

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29600587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PABPN1	NM_004643.4 linkuse as main transcript	c.38C>A	p.Ala13Asp	missense_variant	1/7	ENST00000216727.9	NP_004634.1
BCL2L2-PABPN1	NM_001387343.1 linkuse as main transcript	c.529-674C>A		intron_variant			NP_001374272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PABPN1	ENST00000216727.9 linkuse as main transcript	c.38C>A	p.Ala13Asp	missense_variant	1/7	1	NM_004643.4	ENSP00000216727	P1	Q86U42-1
PABPN1	ENST00000397276.6 linkuse as main transcript	c.38C>A	p.Ala13Asp	missense_variant	1/6	1		ENSP00000380446		Q86U42-2
PABPN1	ENST00000556821.5 linkuse as main transcript			upstream_gene_variant		2		ENSP00000451970

Frequencies

GnomAD3 genomes

AF:

0.00000664

AC:

AN:

150688

Hom.:

Cov.:

show subpopulations

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:

9.26e-7

AC:

AN:

1079704

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

513812

show subpopulations

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:

0.00000109

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000664

AC:

AN:

150688

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73558

show subpopulations

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

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2022

The c.38C>A (p.A13D) alteration is located in exon 1 (coding exon 1) of the PABPN1 gene. This alteration results from a C to A substitution at nucleotide position 38, causing the alanine (A) at amino acid position 13 to be replaced by an aspartic acid (D). 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

0.18

BayesDel_addAF

Benign

0.0093

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.095

T;.

Eigen

Benign

-0.033

Eigen_PC

Benign

0.035

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.50

T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.34

N;N

MutationTaster

Benign

1.0

D;D;N;N

PROVEAN

Benign

-0.23

N;N

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.33

B;P

Vest4

0.36

MutPred

0.21

Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);

MVP

0.54

MPC

1.3

ClinPred

0.64

GERP RS

3.4

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.65

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over