rs735883

Variant names:

• chr6-32848277-G-A
• rs735883
• NM_000593.6:c.1567-185C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000593.6(TAP1):​c.1567-185C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 759,516 control chromosomes in the GnomAD database, including 57,473 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (10859 hom., cov: 33)
  • Exomes 𝑓: 0.39 (46614 hom.)
• Consequence: TAP1 NM_000593.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290
• Publications: 30 publications found

Genes affected

TAP1 (HGNC:43): (transporter 1, ATP binding cassette subfamily B member) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is involved in the pumping of degraded cytosolic peptides across the endoplasmic reticulum into the membrane-bound compartment where class I molecules assemble. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

PSMB9 (HGNC:9546): (proteasome 20S subunit beta 9) The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 1 (proteasome beta 6 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. [provided by RefSeq, Mar 2010]

PSMB9 Gene-Disease associations (from GenCC):

• proteasome-associated autoinflammatory syndrome 3

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAP1	NM_000593.6	c.1567-185C>T		intron_variant	Intron 7 of 10	ENST00000354258.5	NP_000584.3
TAP1	NM_001292022.2	c.964-185C>T		intron_variant	Intron 7 of 10		NP_001278951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAP1	ENST00000354258.5	c.1567-185C>T		intron_variant	Intron 7 of 10	1	NM_000593.6	ENSP00000346206.5

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56883 AN: 151936 Hom.: 10867 Cov.: 33

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.391

GnomAD4 exome AF: 0.385 AC: 234130 AN: 607460 Hom.: 46614 Cov.: 8 AF XY: 0.383 AC XY: 121806 AN XY: 317754

African (AFR) AF: 0.329 AC: 5229 AN: 15880

American (AMR) AF: 0.417 AC: 11506 AN: 27600

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 5901 AN: 17060

East Asian (EAS) AF: 0.354 AC: 11261 AN: 31840

South Asian (SAS) AF: 0.333 AC: 18551 AN: 55746

European-Finnish (FIN) AF: 0.339 AC: 10525 AN: 31038

Middle Eastern (MID) AF: 0.469 AC: 1125 AN: 2400

European-Non Finnish (NFE) AF: 0.400 AC: 157690 AN: 394384

Other (OTH) AF: 0.392 AC: 12342 AN: 31512

GnomAD4 genome AF: 0.374 AC: 56867 AN: 152056 Hom.: 10859 Cov.: 33 AF XY: 0.369 AC XY: 27434 AN XY: 74326

African (AFR) AF: 0.331 AC: 13723 AN: 41458

American (AMR) AF: 0.396 AC: 6045 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1142 AN: 3470

East Asian (EAS) AF: 0.360 AC: 1861 AN: 5168

South Asian (SAS) AF: 0.351 AC: 1691 AN: 4816

European-Finnish (FIN) AF: 0.340 AC: 3590 AN: 10562

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27442 AN: 67984

Other (OTH) AF: 0.386 AC: 815 AN: 2110

Alfa AF: 0.392 Hom.: 10378

Bravo AF: 0.377

Asia WGS AF: 0.319 AC: 1113 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.3
DANN	Benign	0.35
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs735883; hg19: chr6-32816054; COSMIC: COSV62755775;