rs104894466

Variant names:

• chr14-23321504-G-C
• rs104894466
• NM_004643.4:c.35G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004643.4(PABPN1):​c.35G>C​(p.Gly12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PABPN1 NM_004643.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 2.21
• Publications: 8 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PABPN1	NM_004643.4	MANE Select	c.35G>C	p.Gly12Ala	missense	Exon 1 of 7	NP_004634.1
	PABPN1	NM_001360551.3		c.35G>C	p.Gly12Ala	missense	Exon 1 of 6	NP_001347480.1
	BCL2L2-PABPN1	NM_001387340.1		c.550-677G>C		intron	N/A	NP_001374269.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PABPN1	ENST00000216727.9	TSL:1 MANE Select	c.35G>C	p.Gly12Ala	missense	Exon 1 of 7	ENSP00000216727.4
	PABPN1	ENST00000397276.6	TSL:1	c.35G>C	p.Gly12Ala	missense	Exon 1 of 6	ENSP00000380446.2
	BCL2L2-PABPN1	ENST00000553781.5	TSL:2	c.433-677G>C		intron	N/A	ENSP00000451320.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.29e-7 AC: 1 AN: 1075904 Hom.: 0 Cov.: 31 AF XY: 0.00000195 AC XY: 1 AN XY: 511762

African (AFR) AF: 0.00 AC: 0 AN: 22150

American (AMR) AF: 0.00 AC: 0 AN: 7790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13294

East Asian (EAS) AF: 0.00 AC: 0 AN: 25074

South Asian (SAS) AF: 0.00 AC: 0 AN: 19814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2848

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 915508

Other (OTH) AF: 0.0000236 AC: 1 AN: 42312

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Oculopharyngeal muscular dystrophy 1 (2)
1	-	-	PABPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.2
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.092	B
Vest4		0.32
MutPred		0.73		Gain of helix (P = 0.0496)
MVP		0.97
MPC		0.94
ClinPred		0.48	T
GERP RS		3.4
PromoterAI		0.046	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		4.5
Varity_R		0.38
gMVP		0.35
Mutation Taster		=28/72	disease causing (ClinVar)

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: rs104894466; hg19: chr14-23790713;