NM_004643.4:c.31G>A

Variant names:

• chr14-23321500-G-A
• rs1045060319
• NM_004643.4:c.31G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BS2_Supporting

The NM_004643.4(PABPN1):​c.31G>A​(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000467 in 1,070,880 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A11P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (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: 2.82
• Publications: 0 publications found

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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15262693).
• BP6: Variant 14-23321500-G-A is Benign according to our data. Variant chr14-23321500-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1327685.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAdExome4 at 5 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.31G>A	p.Ala11Thr	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.31G>A	p.Ala11Thr	missense_variant	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4
BCL2L2-PABPN1	ENST00000553781.5	c.433-681G>A		intron_variant	Intron 3 of 8	2		ENSP00000451320.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000467 AC: 5 AN: 1070880 Hom.: 0 Cov.: 31 AF XY: 0.00000393 AC XY: 2 AN XY: 509136

African (AFR) AF: 0.00 AC: 0 AN: 22016

American (AMR) AF: 0.00 AC: 0 AN: 7666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13052

East Asian (EAS) AF: 0.0000406 AC: 1 AN: 24602

South Asian (SAS) AF: 0.00 AC: 0 AN: 19668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2818

European-Non Finnish (NFE) AF: 0.00000438 AC: 4 AN: 912914

Other (OTH) AF: 0.00 AC: 0 AN: 42034

GnomAD4 genome Cov.: 32

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

Jan 07, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Apr 16, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.095	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.45	T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		2.8
PROVEAN	Benign	-0.12	N;N
REVEL	Benign	0.067
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.0	B;B
Vest4		0.23
MutPred		0.32		Gain of glycosylation at A11 (P = 0.0075);Gain of glycosylation at A11 (P = 0.0075);
MVP		0.49
MPC		0.85
ClinPred		0.41	T
GERP RS		1.6
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		4.5
Varity_R		0.15
gMVP		0.23
Mutation Taster		=87/13	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

Other links and lift over

dbSNP: rs1045060319; hg19: chr14-23790709;