rs4148882

Variant names:

• chr6-32849181-G-A
• rs4148882
• NM_000593.6:c.1249-63C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000593.6(TAP1):​c.1249-63C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,545,400 control chromosomes in the GnomAD database, including 327,941 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.71 (39080 hom., cov: 31)
  • Exomes 𝑓: 0.64 (288861 hom.)
• Consequence: TAP1 NM_000593.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.776
• Publications: 32 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAP1	NM_000593.6	c.1249-63C>T		intron_variant	Intron 5 of 10	ENST00000354258.5	NP_000584.3
TAP1	NM_001292022.2	c.646-63C>T		intron_variant	Intron 5 of 10		NP_001278951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAP1	ENST00000354258.5	c.1249-63C>T		intron_variant	Intron 5 of 10	1	NM_000593.6	ENSP00000346206.5

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107284 AN: 151958 Hom.: 39034 Cov.: 31

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.731

GnomAD4 exome AF: 0.642 AC: 893929 AN: 1393326 Hom.: 288861 Cov.: 30 AF XY: 0.640 AC XY: 440272 AN XY: 687834

African (AFR) AF: 0.899 AC: 28461 AN: 31666

American (AMR) AF: 0.704 AC: 25181 AN: 35776

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 15043 AN: 25156

East Asian (EAS) AF: 0.595 AC: 21484 AN: 36114

South Asian (SAS) AF: 0.636 AC: 50405 AN: 79250

European-Finnish (FIN) AF: 0.555 AC: 26464 AN: 47688

Middle Eastern (MID) AF: 0.740 AC: 4196 AN: 5674

European-Non Finnish (NFE) AF: 0.637 AC: 684322 AN: 1074066

Other (OTH) AF: 0.662 AC: 38373 AN: 57936

GnomAD4 genome AF: 0.706 AC: 107384 AN: 152074 Hom.: 39080 Cov.: 31 AF XY: 0.698 AC XY: 51866 AN XY: 74320

African (AFR) AF: 0.891 AC: 36992 AN: 41500

American (AMR) AF: 0.689 AC: 10531 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2042 AN: 3472

East Asian (EAS) AF: 0.682 AC: 3517 AN: 5160

South Asian (SAS) AF: 0.654 AC: 3155 AN: 4822

European-Finnish (FIN) AF: 0.547 AC: 5763 AN: 10544

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.633 AC: 43011 AN: 67972

Other (OTH) AF: 0.728 AC: 1540 AN: 2114

Alfa AF: 0.674 Hom.: 40818

Bravo AF: 0.728

Asia WGS AF: 0.649 AC: 2256 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.91
DANN	Benign	0.64
PhyloP100		-0.78
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4148882; hg19: chr6-32816958; COSMIC: COSV62754596; COSMIC: COSV62754596;