rs56366814

Variant names:

• chr6-32850520-G-A
• rs56366814
• NM_000593.6:c.1051-3C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32850520-G-A
• chr6-32850520-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000593.6(TAP1):​c.1051-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,610,784 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (18 hom.)
• Consequence: TAP1 NM_000593.6 splice_region, intron
• Scores: Splicing: ADA: 0.002864
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.896
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 6-32850520-G-A is Benign according to our data. Variant chr6-32850520-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 534731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00289 (440/152358) while in subpopulation AMR AF = 0.00627 (96/15312). AF 95% confidence interval is 0.00526. There are 6 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAP1	NM_000593.6	c.1051-3C>T		splice_region_variant, intron_variant	Intron 4 of 10	ENST00000354258.5	NP_000584.3
TAP1	NM_001292022.2	c.448-3C>T		splice_region_variant, intron_variant	Intron 4 of 10		NP_001278951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAP1	ENST00000354258.5	c.1051-3C>T		splice_region_variant, intron_variant	Intron 4 of 10	1	NM_000593.6	ENSP00000346206.5

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 439 AN: 152240 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00260

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00399 AC: 993 AN: 248714 AF XY: 0.00415

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.00426

Gnomad ASJ exome AF: 0.0308

Gnomad EAS exome AF: 0.000926

Gnomad FIN exome AF: 0.000722

Gnomad NFE exome AF: 0.00299

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00308 AC: 4493 AN: 1458426 Hom.: 18 Cov.: 31 AF XY: 0.00313 AC XY: 2274 AN XY: 725672

African (AFR) AF: 0.000269 AC: 9 AN: 33460

American (AMR) AF: 0.00418 AC: 187 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0298 AC: 780 AN: 26132

East Asian (EAS) AF: 0.000781 AC: 31 AN: 39700

South Asian (SAS) AF: 0.00348 AC: 300 AN: 86238

European-Finnish (FIN) AF: 0.000950 AC: 48 AN: 50510

Middle Eastern (MID) AF: 0.0125 AC: 68 AN: 5442

European-Non Finnish (NFE) AF: 0.00253 AC: 2812 AN: 1111890

Other (OTH) AF: 0.00428 AC: 258 AN: 60336

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152358 Hom.: 6 Cov.: 32 AF XY: 0.00298 AC XY: 222 AN XY: 74520

African (AFR) AF: 0.000601 AC: 25 AN: 41574

American (AMR) AF: 0.00627 AC: 96 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00260 AC: 177 AN: 68042

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00583 Hom.: 2

Bravo AF: 0.00308

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00427

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TAP1: BP4, BS2 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

MHC class I deficiency Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.57
PhyloP100		0.90
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0029
dbscSNV1_RF	Benign	0.32
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: rs56366814; hg19: chr6-32818297;