rs192572056
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000593.6(TAP1):c.1601C>T(p.Thr534Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,612,430 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T534T) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000034 ( 2 hom. )
Consequence
TAP1
NM_000593.6 missense
NM_000593.6 missense
Scores
1
11
6
Clinical Significance
Conservation
PhyloP100: 0.712
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
?
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TAP1 | NM_000593.6 | c.1601C>T | p.Thr534Met | missense_variant | 8/11 | ENST00000354258.5 | |
TAP1 | NM_001292022.2 | c.998C>T | p.Thr333Met | missense_variant | 8/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TAP1 | ENST00000354258.5 | c.1601C>T | p.Thr534Met | missense_variant | 8/11 | 1 | NM_000593.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152240Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000492 AC: 12AN: 243986Hom.: 1 AF XY: 0.0000601 AC XY: 8AN XY: 133182
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GnomAD4 exome AF: 0.0000336 AC: 49AN: 1460072Hom.: 2 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 726360
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GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152358Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74512
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
MHC class I deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 594 of the TAP1 protein (p.Thr594Met). This variant is present in population databases (rs192572056, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 582193). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at