14-23321506-G-C

Variant names:

• chr14-23321506-G-C
• rs1293492884
• NM_004643.4:c.37G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4 BS2_Supporting

The NM_004643.4(PABPN1):​c.37G>C​(p.Ala13Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 1,079,142 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: PABPN1 NM_004643.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.18

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: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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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=0.34433997).
• BS2: High AC in GnomAdExome4 at 45 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1	NM_004643.4	c.37G>C	p.Ala13Pro	missense_variant	Exon 1 of 7	ENST00000216727.9	NP_004634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABPN1	ENST00000216727.9	c.37G>C	p.Ala13Pro	missense_variant	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4
BCL2L2-PABPN1	ENST00000678502.1	c.529-675G>C		intron_variant	Intron 4 of 9			ENSP00000503309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000417 AC: 45 AN: 1079142 Hom.: 0 Cov.: 31 AF XY: 0.0000389 AC XY: 20 AN XY: 513622

African (AFR) AF: 0.00 AC: 0 AN: 22214

American (AMR) AF: 0.00 AC: 0 AN: 7854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13356

East Asian (EAS) AF: 0.00 AC: 0 AN: 25210

South Asian (SAS) AF: 0.00 AC: 0 AN: 20002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2860

European-Non Finnish (NFE) AF: 0.0000392 AC: 36 AN: 917736

Other (OTH) AF: 0.000212 AC: 9 AN: 42466

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.37G>C (p.A13P) 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 37, causing the alanine (A) at amino acid position 13 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Oculopharyngeal muscular dystrophy Uncertain:1

Feb 18, 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	0.11
BayesDel_addAF	Benign	0.0036	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.095	T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.54	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.34	N;N
PhyloP100		2.2
PROVEAN	Benign	-0.41	N;N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.84	P;P
Vest4		0.30
MutPred		0.25		Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);
MVP		0.44
MPC		1.1
ClinPred		0.53	D
GERP RS		3.4
PromoterAI		0.22	Neutral
Varity_R		0.59
gMVP		0.41
Mutation Taster		=58/42	polymorphism

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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Other links and lift over

dbSNP: rs1293492884; hg19: chr14-23790715;