chr14-23321493-A-G

Variant names:

• chr14-23321493-A-G
• rs1052657001
• NM_004643.4:c.24A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The NM_004643.4(PABPN1):​c.24A>G​(p.Ala8Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,205,366 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: PABPN1 NM_004643.4 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09
• 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 (BayesDel_noAF=-0.44).
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1	NM_004643.4	c.24A>G	p.Ala8Ala	synonymous_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.24A>G	p.Ala8Ala	synonymous_variant	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4
BCL2L2-PABPN1	ENST00000553781.5	c.433-688A>G		intron_variant	Intron 3 of 8	2		ENSP00000451320.1

Frequencies

GnomAD3 genomes AF: 0.0000464 AC: 7 AN: 150724 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

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: 0.0000444

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000664 AC: 7 AN: 1054642 Hom.: 0 Cov.: 31 AF XY: 0.00000999 AC XY: 5 AN XY: 500744

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

African (AFR) AF: 0.0000925 AC: 2 AN: 21620

American (AMR) AF: 0.00 AC: 0 AN: 7280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12592

East Asian (EAS) AF: 0.00 AC: 0 AN: 23464

South Asian (SAS) AF: 0.00 AC: 0 AN: 19454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2764

European-Non Finnish (NFE) AF: 0.00000443 AC: 4 AN: 902158

Other (OTH) AF: 0.0000243 AC: 1 AN: 41070

⚠️ 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.

GnomAD4 genome AF: 0.0000464 AC: 7 AN: 150724 Hom.: 0 Cov.: 32 AF XY: 0.0000543 AC XY: 4 AN XY: 73598

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

African (AFR) AF: 0.0000970 AC: 4 AN: 41242

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67552

Other (OTH) AF: 0.00 AC: 0 AN: 2068

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000045), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 15, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.75
PhyloP100		1.1
PromoterAI		-0.00020	Neutral

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: rs1052657001; hg19: chr14-23790702;