14-23321506-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_004643.4(PABPN1):​c.37G>A​(p.Ala13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000741 in 1,079,138 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: PABPN1 NM_004643.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.18
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2967897).
• BS2: High AC in GnomAdExome4 at 8 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>A	p.Ala13Thr	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>A	p.Ala13Thr	missense_variant	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4
BCL2L2-PABPN1	ENST00000553781.5	c.433-675G>A		intron_variant	Intron 3 of 8	2		ENSP00000451320.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000741 AC: 8 AN: 1079138 Hom.: 0 Cov.: 31 AF XY: 0.00000584 AC XY: 3 AN XY: 513620

African (AFR) AF: 0.0000450 AC: 1 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: 0.00000763 AC: 7 AN: 917736

Other (OTH) AF: 0.00 AC: 0 AN: 42462

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T;.
Eigen	Benign	0.037
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.58	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.34	N;N
PhyloP100		2.2
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.086
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.33	B;P
Vest4		0.24
MutPred		0.23		Gain of glycosylation at A13 (P = 0.0071);Gain of glycosylation at A13 (P = 0.0071);
MVP		0.53
MPC		0.85
ClinPred		0.64	D
GERP RS		3.4
PromoterAI		0.076	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		4.5
Varity_R		0.34
gMVP		0.29
Mutation Taster		=64/36	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: rs1293492884; hg19: chr14-23790715;