Genetic Variant PABPN1:p.Ala7_Ala8del (chr14-23321471-TGGCGGC-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_004643.4(PABPN1):c.18_23delGGCGGC(p.Ala7_Ala8del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000199 in 1,004,954 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000020 ( 0 hom. )

Consequence

PABPN1
NM_004643.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.49

Publications

1 publications found

Variant links:

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]

PABPN1 links:

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]

BCL2L2-PABPN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1	NM_004643.4 link	c.18_23delGGCGGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 7	ENST00000216727.9	NP_004634.1	Q86U42-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABPN1	ENST00000216727.9 link	c.18_23delGGCGGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4		Q86U42-1
BCL2L2-PABPN1	ENST00000553781.5 link	c.433-694_433-689delGGCGGC		intron_variant	Intron 3 of 8	2		ENSP00000451320.1		Q92843-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000199

AC:

AN:

1004954

Hom.:

AF XY:

0.00000210

AC XY:

AN XY:

476172

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

19974

American (AMR)

AF:

0.00

AC:

AN:

5794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10610

East Asian (EAS)

AF:

0.00

AC:

AN:

17698

South Asian (SAS)

AF:

0.00

AC:

AN:

18946

European-Finnish (FIN)

AF:

0.0000552

AC:

AN:

18116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2592

European-Non Finnish (NFE)

AF:

0.00000114

AC:

AN:

873470

Other (OTH)

AF:

0.00

AC:

AN:

37754

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.5

Mutation Taster

=116/84

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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14-23321471-TGGCGGC-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over