rs554237124
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000593.6(TAP1):c.-59C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000401 in 1,570,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
TAP1
NM_000593.6 5_prime_UTR
NM_000593.6 5_prime_UTR
Scores
2
1
15
Clinical Significance
Conservation
PhyloP100: -0.0800
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 -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.040513933).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TAP1 | NM_000593.6 | c.-59C>T | 5_prime_UTR_variant | 1/11 | ENST00000354258.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TAP1 | ENST00000354258.5 | c.-59C>T | 5_prime_UTR_variant | 1/11 | 1 | NM_000593.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000210 AC: 32AN: 152210Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000233 AC: 4AN: 171422Hom.: 0 AF XY: 0.0000210 AC XY: 2AN XY: 95234
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GnomAD4 exome AF: 0.0000219 AC: 31AN: 1418570Hom.: 0 Cov.: 33 AF XY: 0.0000171 AC XY: 12AN XY: 702716
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GnomAD4 genome ? AF: 0.000210 AC: 32AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74476
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
MHC class I deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 41 of the TAP1 protein (p.Pro41Leu). This variant is present in population databases (rs554237124, gnomAD 0.06%). 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: 466376). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 10, 2022 | The c.122C>T (p.P41L) alteration is located in exon 1 (coding exon 1) of the TAP1 gene. This alteration results from a C to T substitution at nucleotide position 122, causing the proline (P) at amino acid position 41 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Benign
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;.
Polyphen
B;.
Vest4
MutPred
Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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