14-23321500-G-T

Variant names:

• chr14-23321500-G-T
• rs1045060319
• NM_004643.4:c.31G>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.31G>T​(p.Ala11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000573 in 1,221,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. A11T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: PABPN1 NM_004643.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.82
• Publications: 1 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=0.08301988).
• 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>T	p.Ala11Ser	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>T	p.Ala11Ser	missense_variant	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4
BCL2L2-PABPN1	ENST00000553781.5	c.433-681G>T		intron_variant	Intron 3 of 8	2		ENSP00000451320.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150786 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000467 AC: 5 AN: 1070880 Hom.: 0 Cov.: 31 AF XY: 0.00000589 AC XY: 3 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: 0.00 AC: 0 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: 0.00000548 AC: 5 AN: 912914

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

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150786 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73602

African (AFR) AF: 0.00 AC: 0 AN: 41288

American (AMR) AF: 0.00 AC: 0 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67566

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.095	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.47	T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.083	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		2.8
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.028
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.25	T;T
Polyphen		0.0060	B;B
Vest4		0.19
MutPred		0.33		Gain of glycosylation at A11 (P = 2e-04);Gain of glycosylation at A11 (P = 2e-04);
MVP		0.51
MPC		0.80
ClinPred		0.27	T
GERP RS		1.6
PromoterAI		-0.091	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		4.5
Varity_R		0.20
gMVP		0.21
Mutation Taster		=86/14	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;