6-32845746-G-C

Variant names:

• chr6-32845746-G-C
• rs563899405
• NM_000593.6:c.2080C>G
• TAP1 p.Arg694Gly

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000593.6(TAP1):c.2080C>G (p.Arg694Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000685 (AC=1) in the gnomAD database across 1,460,560 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R694C: Uncertain_significance (ClinVar VariationId 1516556, 1 star); p.R694H: Uncertain_significance (ClinVar VariationId 1384330, 1 star)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Not reported in ClinVar
• 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): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AR gene (threshold 0.001) — PM2 moderate.

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>G p.Arg694Gly	missense	Exon 11 of 11	Prot: NP_000584.3
	TAP1 NM_001292022.2		c.1477C>G p.Arg493Gly	missense	Exon 11 of 11	Prot: NP_001278951.1
	PSMB8-AS1 NR_037173.1		n.744G>C	non_coding_transcript_exon	Exon 3 of 3	Prot:

TAP1 NM_000593.6

MANE Select

HGVSc / HGVSpc.2080C>Gp.Arg694Gly

Exon rankExon 11 of 11

missense

Prot: NP_000584.3

TAP1 NM_001292022.2

HGVSc / HGVSpc.1477C>Gp.Arg493Gly

Exon rankExon 11 of 11

missense

Prot: NP_001278951.1

PSMB8-AS1 NR_037173.1

HGVSc / HGVSpn.744G>C

Exon rankExon 3 of 3

non_coding_transcript_exon

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TAP1 ENST00000354258.5	TSL:1MANE Select	c.2080C>G p.Arg694Gly	missense	Exon 11 of 11	Prot: ENSP00000346206.5 UniProt:
	TAP1 ENST00000920268.1		c.2092C>G p.Arg698Gly	missense	Exon 11 of 11	Prot: ENSP00000590327.1 UniProt:
	TAP1 ENST00000875705.1		c.2062C>G p.Arg688Gly	missense	Exon 11 of 11	Prot: ENSP00000545764.1 UniProt:

TAP1 ENST00000354258.5

TSL:1MANE Select

HGVSc / HGVSpc.2080C>Gp.Arg694Gly

Exon rankExon 11 of 11

missense

Prot: ENSP00000346206.5UniProt: Q03518-1

TAP1 ENST00000920268.1

HGVSc / HGVSpc.2092C>Gp.Arg698Gly

Exon rankExon 11 of 11

missense

Prot: ENSP00000590327.1UniProt: A0ACI8T119

TAP1 ENST00000875705.1

HGVSc / HGVSpc.2062C>Gp.Arg688Gly

Exon rankExon 11 of 11

missense

Prot: ENSP00000545764.1UniProt: 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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 6.85e-7	AC:1	Hom:0	AN:1460560	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:37854	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000413	2	48444	0.00	0	74538

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	20
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.078
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.51	D
FuncVEP CTI	Pathogenic	0.85
GPN-Star LLR	N/A	-6.6
GPN-Star score	N/A	6.6
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.43	T
Mutation Taster	N/A	78/22	polymorphism
MutationAssessor	Benign	1.8	L
PhyloP100	Benign	1.8
popEVE	Benign	-3.6
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Varity_R	N/A	0.28
VESM-3B	Benign	-8.7

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs563899405;

hg19: chr6-32813523;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar