ENST00000666376.1:n.1021T>C

Variant names:

• chr6-32845139-T-C
• rs2071540
• ENST00000666376.1:n.1021T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000666376.1(PSMB8-AS1):​n.1021T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.599 in 255,686 control chromosomes in the GnomAD database, including 46,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.61 (28925 hom., cov: 33)
  • Exomes 𝑓: 0.58 (17945 hom.)
• Consequence: PSMB8-AS1 ENST00000666376.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.98
• Publications: 43 publications found

Genes affected

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]

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: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• MHC class I deficiency 1

  Inheritance: AR Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 6-32845139-T-C is Benign according to our data. Variant chr6-32845139-T-C is described in ClinVar as Benign. ClinVar VariationId is 1271041.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAP1	NM_000593.6	c.*440A>G		downstream_gene_variant		ENST00000354258.5	NP_000584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAP1	ENST00000354258.5	c.*440A>G		downstream_gene_variant		1	NM_000593.6	ENSP00000346206.5

Frequencies

GnomAD3 genomes AF: 0.612 AC: 93082 AN: 151972 Hom.: 28892 Cov.: 33

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.678

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.606

GnomAD4 exome AF: 0.578 AC: 59869 AN: 103596 Hom.: 17945 AF XY: 0.580 AC XY: 32388 AN XY: 55814

African (AFR) AF: 0.687 AC: 2129 AN: 3100

American (AMR) AF: 0.597 AC: 2664 AN: 4466

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1279 AN: 2398

East Asian (EAS) AF: 0.657 AC: 3210 AN: 4886

South Asian (SAS) AF: 0.603 AC: 10874 AN: 18032

European-Finnish (FIN) AF: 0.545 AC: 1835 AN: 3366

Middle Eastern (MID) AF: 0.693 AC: 233 AN: 336

European-Non Finnish (NFE) AF: 0.560 AC: 34726 AN: 62064

Other (OTH) AF: 0.590 AC: 2919 AN: 4948

GnomAD4 genome AF: 0.613 AC: 93164 AN: 152090 Hom.: 28925 Cov.: 33 AF XY: 0.610 AC XY: 45323 AN XY: 74348

African (AFR) AF: 0.697 AC: 28894 AN: 41476

American (AMR) AF: 0.579 AC: 8850 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1920 AN: 3466

East Asian (EAS) AF: 0.678 AC: 3512 AN: 5178

South Asian (SAS) AF: 0.639 AC: 3084 AN: 4824

European-Finnish (FIN) AF: 0.540 AC: 5706 AN: 10566

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39164 AN: 67972

Other (OTH) AF: 0.604 AC: 1277 AN: 2114

Alfa AF: 0.601 Hom.: 58558

Bravo AF: 0.618

Asia WGS AF: 0.628 AC: 2186 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: 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	-0.98
CADD	Benign	0.83
DANN	Benign	0.39
PhyloP100		-3.0
PromoterAI		-0.038	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2071540; hg19: chr6-32812916;