TAP1 p.Arg694Cys

Variant names:

• chr6-32845746-G-A
• rs563899405
• NM_000593.6:c.2080C>T
• TAP1 p.Arg694Cys

Your query was ambiguous. Multiple possible variants found:

• chr6-32845746-G-A
• chr6-32845744-GCG-ACA

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2_Supporting

The NM_000593.6(TAP1):c.2080C>T (p.Arg694Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000223 (AC=36) in the gnomAD database across 1,612,860 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000207. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R694H: Uncertain_significance (ClinVar VariationId 1384330, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78
• Publications: 0 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]

TAP1 Gene-Disease associations (from GenCC):

• MHC class I deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• MHC class I deficiency 1

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia

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 6

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• proteasome-associated autoinflammatory syndrome 3

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

PSMB8-AS1 (HGNC:39758): (PSMB8 antisense RNA 1 (head to head))

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000207 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000593.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	NM_000593.6	MANE Select	c.2080C>T	p.Arg694Cys	missense	Exon 11 of 11	NP_000584.3
	TAP1	NM_001292022.2		c.1477C>T	p.Arg493Cys	missense	Exon 11 of 11	NP_001278951.1
	PSMB8-AS1	NR_037173.1		n.744G>A		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	ENST00000354258.5	TSL:1 MANE Select	c.2080C>T	p.Arg694Cys	missense	Exon 11 of 11	ENSP00000346206.5	Q03518-1
	TAP1	ENST00000920268.1		c.2092C>T	p.Arg698Cys	missense	Exon 11 of 11	ENSP00000590327.1	A0ACI8T119
	TAP1	ENST00000875705.1		c.2062C>T	p.Arg688Cys	missense	Exon 11 of 11	ENSP00000545764.1	A0ACI8QHR4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152182	Cov:32
GnomAD2 exomes	AF: 0.0000326	AC:8	Hom:	AN:245728	Cov:
GnomAD4 exome	AF: 0.0000233	AC:34	Hom:0	AN:1460560	Cov:31
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152300	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000264	AC:1	Hom:0	AN:37854	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000410	AC:5	Hom:0	AN:122096	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
Epi25(Epilepsy)	0.00	0	41956	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000775	8	103218	0.0000542	10	184432

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	MHC class I deficiency (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	18
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.34	N
FuncVEP CTI	Benign	0.12
GPN-Star LLR	N/A	-5.3
GPN-Star score	N/A	5.3
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.75	T
Mutation Taster	N/A	78/22	polymorphism
MutationAssessor	Benign	1.4	L
PhyloP100	Benign	1.8
popEVE	Benign	-3.2
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.42
Sift	Benign	0.075	T
Sift4G	Pathogenic	0.0010	D
Varity_R	N/A	0.18
VESM-3B	Benign	-6.7

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs563899405;

hg19: chr6-32813523;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar