Genetic Variant TAP1:p.Pro747Ser (chr6-32845585-TGG-GCT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_000593.6(TAP1):c.2239_2241delCCAinsAGC (p.Pro747Ser) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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.P747S: Uncertain_significance (ClinVar VariationId 2573443, 2 stars)

Frequency

Genomes: not found (cov: 32)

Consequence

TAP1
NM_000593.6 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.789

Publications

0 publications found

Variant links:

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

TAP1 links:

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

PSMB9 links:

PSMB8-AS1 (HGNC:39758): ()

PSMB8-AS1 links:

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new If you want to explore the variant's impact on the transcript NM_000593.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (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

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
TAP1 NM_000593.6	MANE Select	c.2239_2241delCCAinsAGC p.Pro747Ser	missense	N/A	Prot: NP_000584.3
TAP1 NM_001292022.2		c.1636_1638delCCAinsAGC p.Pro546Ser	missense	N/A	Prot: NP_001278951.1
PSMB8-AS1 NR_037173.1		n.583_585delTGGinsGCT	non_coding_transcript_exon	Exon 3 of 3	Prot:

TAP1 NM_000593.6

MANE Select

HGVSc / HGVSpc.2239_2241delCCAinsAGCp.Pro747Ser

Exon rankN/A

missense

Prot: NP_000584.3

TAP1 NM_001292022.2

HGVSc / HGVSpc.1636_1638delCCAinsAGCp.Pro546Ser

Exon rankN/A

missense

Prot: NP_001278951.1

PSMB8-AS1 NR_037173.1

HGVSc / HGVSpn.583_585delTGGinsGCT

Exon rankExon 3 of 3

non_coding_transcript_exon

Prot:

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
TAP1 ENST00000354258.5	TSL:1MANE Select	c.2239_2241delCCAinsAGC p.Pro747Ser	missense	N/A	Prot: ENSP00000346206.5 UniProt: Q03518-1
TAP1 ENST00000698423.1		c.2334_2336delCCAinsAGC p.Gln779Ala	missense	N/A	Prot: ENSP00000513711.1 UniProt: A0A8V8TM76
TAP1 ENST00000920268.1		c.2251_2253delCCAinsAGC p.Pro751Ser	missense	N/A	Prot: ENSP00000590327.1 UniProt: A0ACI8T119

TAP1 ENST00000354258.5

TSL:1MANE Select

HGVSc / HGVSpc.2239_2241delCCAinsAGCp.Pro747Ser

Exon rankN/A

missense

Prot: ENSP00000346206.5UniProt: Q03518-1

TAP1 ENST00000698423.1

HGVSc / HGVSpc.2334_2336delCCAinsAGCp.Gln779Ala

Exon rankN/A

missense

Prot: ENSP00000513711.1UniProt: A0A8V8TM76

TAP1 ENST00000920268.1

HGVSc / HGVSpc.2251_2253delCCAinsAGCp.Pro751Ser

Exon rankN/A

missense

Prot: ENSP00000590327.1UniProt: A0ACI8T119

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.79

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence