14-23321471-TGGCGGCGGCGGCGGC-TGGCGGCGGC

Variant names:

• chr14-23321471-TGGCGGC-T
• rs193922941
• NM_004643.4:c.18_23delGGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.49
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_004643.4

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.18_23delGGCGGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 7	NP_004634.1	Q86U42-1
	PABPN1	NM_001360551.3		c.18_23delGGCGGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 6	NP_001347480.1	Q86U42-2
	BCL2L2-PABPN1	NM_001387340.1		c.550-694_550-689delGGCGGC		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.18_23delGGCGGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000216727.4	Q86U42-1
	PABPN1	ENST00000397276.6	TSL:1	c.18_23delGGCGGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000380446.2	Q86U42-2
	BCL2L2-PABPN1	ENST00000553781.5	TSL:2	c.433-694_433-689delGGCGGC		intron	N/A	ENSP00000451320.1	Q92843-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000199 AC: 2 AN: 1004954 Hom.: 0 AF XY: 0.00000210 AC XY: 1 AN XY: 476172

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

African (AFR) AF: 0.00 AC: 0 AN: 19974

American (AMR) AF: 0.00 AC: 0 AN: 5794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10610

East Asian (EAS) AF: 0.00 AC: 0 AN: 17698

South Asian (SAS) AF: 0.00 AC: 0 AN: 18946

European-Finnish (FIN) AF: 0.0000552 AC: 1 AN: 18116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2592

European-Non Finnish (NFE) AF: 0.00000114 AC: 1 AN: 873470

Other (OTH) AF: 0.00 AC: 0 AN: 37754

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=116/84	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs193922941; hg19: chr14-23790680;