chr14-23321471-TGGCGGC-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

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. Variant has been reported in Lovd as Pathogenic (no stars).

• 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

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

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a region_of_interest Interaction with SKIP (size 143) in uniprot entity PABP2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_004643.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-23321471-TGGCGGC-T is Pathogenic according to our data. Variant chr14-23321471-TGGCGGC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1	NM_004643.4	c.18_23delGGCGGC	p.Ala7_Ala8del	disruptive_inframe_deletion	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.18_23delGGCGGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 7	1	NM_004643.4	ENSP00000216727.4
BCL2L2-PABPN1	ENST00000678502.1	c.529-694_529-689delGGCGGC		intron_variant	Intron 4 of 9			ENSP00000503309.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000552

Gnomad4 NFE exome AF: 0.00000114

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922941; hg19: chr14-23790680;