rs550037204

Variant names:

• chr6-32852472-C-T
• rs550037204
• NM_000593.6:c.629G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000593.6(TAP1):​c.629G>A​(p.Arg210His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000098 in 1,612,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.687
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21638307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAP1	NM_000593.6	c.629G>A	p.Arg210His	missense_variant	Exon 2 of 11	ENST00000354258.5	NP_000584.3
TAP1	NM_001292022.2	c.26G>A	p.Arg9His	missense_variant	Exon 2 of 11		NP_001278951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAP1	ENST00000354258.5	c.629G>A	p.Arg210His	missense_variant	Exon 2 of 11	1	NM_000593.6	ENSP00000346206.5

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000852 AC: 21 AN: 246610 AF XY: 0.0000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000181

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000945 AC: 138 AN: 1460774 Hom.: 0 Cov.: 33 AF XY: 0.0000853 AC XY: 62 AN XY: 726702

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52316

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1112008

Other (OTH) AF: 0.000116 AC: 7 AN: 60386

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41496

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000149 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.000111 AC: 13

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class I deficiency Uncertain:1

Jul 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 270 of the TAP1 protein (p.Arg270His). This variant is present in population databases (rs550037204, gnomAD 0.02%). 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: 582202). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.69
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.27
Sift	Benign	0.068	T
Sift4G	Benign	0.13	T
Polyphen		0.23	B
Vest4		0.20
MVP		0.80
MPC		1.0
ClinPred		0.15	T
GERP RS		1.8
Varity_R		0.073
gMVP		0.69
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs550037204; hg19: chr6-32820249;