6-32845503-T-G

Position:

• chr6-32845503-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000593.6(TAP1):​c.*76A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,498,874 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (43 hom.)
• Consequence: TAP1 NM_000593.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.464

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-32845503-T-G is Benign according to our data. Variant chr6-32845503-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3024794.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00285 (434/152280) while in subpopulation SAS AF= 0.00518 (25/4824). AF 95% confidence interval is 0.0036. There are 2 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAP1	NM_000593.6	c.*76A>C		3_prime_UTR_variant	11/11	ENST00000354258.5	NP_000584.3
PSMB8-AS1	NR_037173.1	n.501T>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAP1	ENST00000354258.5	c.*76A>C		3_prime_UTR_variant	11/11	1	NM_000593.6	ENSP00000346206	P1
PSMB8-AS1	ENST00000453426.2	n.275T>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 439 AN: 152162 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00423 AC: 5698 AN: 1346594 Hom.: 43 Cov.: 24 AF XY: 0.00443 AC XY: 2986 AN XY: 674624

Gnomad4 AFR exome AF: 0.000865

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.0167

Gnomad4 EAS exome AF: 0.000360

Gnomad4 SAS exome AF: 0.00845

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.00378

Gnomad4 OTH exome AF: 0.00554

GnomAD4 genome AF: 0.00285 AC: 434 AN: 152280 Hom.: 2 Cov.: 32 AF XY: 0.00277 AC XY: 206 AN XY: 74462

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00356

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00307 Hom.: 0

Bravo AF: 0.00291

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

TAP1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	10
DANN	Benign	0.69
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: rs541148983; hg19: chr6-32813280; COSMIC: COSV62753670; COSMIC: COSV62753670;