rs4148882

chr6-32849181-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
TAP1	NM_000593.6	c.1249-63C>T		intron_variant		ENST00000354258.5
TAP1	NM_001292022.2	c.646-63C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP1	ENST00000354258.5	c.1249-63C>T		intron_variant		1	NM_000593.6	P1

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

Gnomad4 AFR exome AF: 0.899

Gnomad4 AMR exome AF: 0.704

Gnomad4 ASJ exome AF: 0.598

Gnomad4 EAS exome AF: 0.595

Gnomad4 SAS exome AF: 0.636

Gnomad4 FIN exome AF: 0.555

Gnomad4 NFE exome AF: 0.637

Gnomad4 OTH exome AF: 0.662

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

Gnomad4 AFR AF: 0.891

Gnomad4 AMR AF: 0.689

Gnomad4 ASJ AF: 0.588

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.654

Gnomad4 FIN AF: 0.547

Gnomad4 NFE AF: 0.633

Gnomad4 OTH AF: 0.728

Alfa AF: 0.643 Hom.: 24892

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs4148882; hg19: chr6-32816958; COSMIC: COSV62754596; COSMIC: COSV62754596;