6-33304121-CACTT-C

Variant names:

• chr6-33304121-CACTT-C
• rs770150271
• NM_003190.5:c.1300+3_1300+6delAAGT

Variant summary

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

The NM_003190.5(TAPBP):​c.1300+3_1300+6delAAGT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000415 in 1,612,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: TAPBP NM_003190.5 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

Genes affected

TAPBP (HGNC:11566): (TAP binding protein) This gene encodes a transmembrane glycoprotein which mediates interaction between newly assembled major histocompatibility complex (MHC) class I molecules and the transporter associated with antigen processing (TAP), which is required for the transport of antigenic peptides across the endoplasmic reticulum membrane. This interaction is essential for optimal peptide loading on the MHC class I molecule. Up to four complexes of MHC class I and this protein may be bound to a single TAP molecule. This protein contains a C-terminal double-lysine motif (KKKAE) known to maintain membrane proteins in the endoplasmic reticulum. This gene lies within the major histocompatibility complex on chromosome 6. Alternative splicing results in three transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAPBP	NM_003190.5	c.1300+3_1300+6delAAGT		splice_region_variant, intron_variant	Intron 6 of 7	ENST00000434618.7	NP_003181.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAPBP	ENST00000434618.7	c.1300+3_1300+6delAAGT		splice_region_variant, intron_variant	Intron 6 of 7	1	NM_003190.5	ENSP00000395701.2

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151466 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000599 AC: 15 AN: 250542 AF XY: 0.0000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000411 AC: 60 AN: 1461254 Hom.: 0 AF XY: 0.0000426 AC XY: 31 AN XY: 726906

Gnomad4 AFR exome AF: 0.000239 AC: 8 AN: 33472

Gnomad4 AMR exome AF: 0.0000672 AC: 3 AN: 44672

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26060

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39696

Gnomad4 SAS exome AF: 0.000244 AC: 21 AN: 86176

Gnomad4 FIN exome AF: 0.0000562 AC: 3 AN: 53390

Gnomad4 NFE exome AF: 0.0000162 AC: 18 AN: 1111664

Gnomad4 Remaining exome AF: 0.0000828 AC: 5 AN: 60358

GnomAD4 genome AF: 0.0000462 AC: 7 AN: 151584 Hom.: 0 Cov.: 31 AF XY: 0.0000810 AC XY: 6 AN XY: 74086

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.0000658 AC: 0.0000657808 AN: 0.0000657808

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000625 AC: 0.00062474 AN: 0.00062474

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000442 AC: 0.0000441956 AN: 0.0000441956

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class I deficiency Uncertain:1

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 6 of the TAPBP gene. It does not directly change the encoded amino acid sequence of the TAPBP protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs770150271, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TAPBP-related conditions. ClinVar contains an entry for this variant (Variation ID: 649689). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs770150271; hg19: chr6-33271898;