rs3198005

Positions:

• chr6-32845437-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.*142C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 793,664 control chromosomes in the GnomAD database, including 884 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 0.035 (136 hom., cov: 32)
  • Exomes 𝑓: 0.042 (748 hom.)
• Consequence: TAP1 NM_000593.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.689

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]

PSMB8-AS1 (HGNC:39758): (PSMB8 antisense RNA 1 (head to head))

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=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP1	NM_000593.6	c.*142C>T		3_prime_UTR_variant	11/11	ENST00000354258.5
PSMB8-AS1	NR_037173.1	n.435G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP1	ENST00000354258.5	c.*142C>T		3_prime_UTR_variant	11/11	1	NM_000593.6	P1
PSMB8-AS1	ENST00000453426.2	n.209G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5259 AN: 152108 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.00896

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.0338

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0544

Gnomad OTH AF: 0.0277

GnomAD4 exome AF: 0.0421 AC: 27008 AN: 641438 Hom.: 748 Cov.: 8 AF XY: 0.0415 AC XY: 14164 AN XY: 341046

Gnomad4 AFR exome AF: 0.00798

Gnomad4 AMR exome AF: 0.0231

Gnomad4 ASJ exome AF: 0.0237

Gnomad4 EAS exome AF: 0.00117

Gnomad4 SAS exome AF: 0.0204

Gnomad4 FIN exome AF: 0.0375

Gnomad4 NFE exome AF: 0.0536

Gnomad4 OTH exome AF: 0.0412

GnomAD4 genome AF: 0.0346 AC: 5260 AN: 152226 Hom.: 136 Cov.: 32 AF XY: 0.0341 AC XY: 2540 AN XY: 74418

Gnomad4 AFR AF: 0.00891

Gnomad4 AMR AF: 0.0362

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.0193

Gnomad4 FIN AF: 0.0338

Gnomad4 NFE AF: 0.0544

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0465 Hom.: 252

Bravo AF: 0.0330

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.3
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3198005; hg19: chr6-32813214;