14-23321507-C-T

Variant names:

• chr14-23321507-C-T
• rs1888259528
• NM_004643.4:c.38C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_004643.4(PABPN1):​c.38C>T​(p.Ala13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,079,704 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. A13P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PABPN1 NM_004643.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41
• 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2561459).
• BS2: High AC in GnomAdExome4 at 12 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004643.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PABPN1	NM_004643.4	MANE Select	c.38C>T	p.Ala13Val	missense	Exon 1 of 7	NP_004634.1	Q86U42-1
	PABPN1	NM_001360551.3		c.38C>T	p.Ala13Val	missense	Exon 1 of 6	NP_001347480.1	Q86U42-2
	BCL2L2-PABPN1	NM_001387340.1		c.550-674C>T		intron	N/A	NP_001374269.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PABPN1	ENST00000216727.9	TSL:1 MANE Select	c.38C>T	p.Ala13Val	missense	Exon 1 of 7	ENSP00000216727.4	Q86U42-1
	PABPN1	ENST00000397276.6	TSL:1	c.38C>T	p.Ala13Val	missense	Exon 1 of 6	ENSP00000380446.2	Q86U42-2
	BCL2L2-PABPN1	ENST00000553781.5	TSL:2	c.433-674C>T		intron	N/A	ENSP00000451320.1	Q92843-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000111 AC: 12 AN: 1079704 Hom.: 0 Cov.: 30 AF XY: 0.00000778 AC XY: 4 AN XY: 513812

African (AFR) AF: 0.00 AC: 0 AN: 22230

American (AMR) AF: 0.00 AC: 0 AN: 7902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13408

East Asian (EAS) AF: 0.00 AC: 0 AN: 25308

South Asian (SAS) AF: 0.00 AC: 0 AN: 20020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2862

European-Non Finnish (NFE) AF: 0.0000109 AC: 10 AN: 917872

Other (OTH) AF: 0.0000471 AC: 2 AN: 42500

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Oculopharyngeal muscular dystrophy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.0071	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.034
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.4
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.33	B
Vest4		0.22
MutPred		0.30		Gain of catalytic residue at A13 (P = 0.0039)
MVP		0.61
MPC		0.87
ClinPred		0.63	D
GERP RS		3.4
PromoterAI		0.054	Neutral
Varity_R		0.32
gMVP		0.32
Mutation Taster		=69/31	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: rs1888259528; hg19: chr14-23790716;