6-32853805-A-C

Variant names:

• chr6-32853805-A-C
• rs148176741
• ENST00000643049.2:c.-169T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000643049.2(TAP1):​c.-169T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,549,194 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: TAP1 ENST00000643049.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.78
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-32853805-A-C is Benign according to our data. Variant chr6-32853805-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 534720.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00109 (166/152112) while in subpopulation NFE AF = 0.00179 (122/67972). AF 95% confidence interval is 0.00154. There are 0 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000643049.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	NM_000593.6	MANE Select	c.-169T>G		upstream_gene	N/A	NP_000584.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	ENST00000643049.2		c.-169T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000494148.2
	TAP1	ENST00000643049.2		c.-169T>G		5_prime_UTR	Exon 1 of 5	ENSP00000494148.2
	PSMB9	ENST00000395330.6	TSL:3	c.-9-2333A>C		intron	N/A	ENSP00000378739.1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 151994 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00102 AC: 151 AN: 148164 AF XY: 0.00106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.000604

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00167 AC: 2334 AN: 1397082 Hom.: 3 Cov.: 33 AF XY: 0.00162 AC XY: 1122 AN XY: 690902

African (AFR) AF: 0.000218 AC: 7 AN: 32072

American (AMR) AF: 0.000882 AC: 33 AN: 37430

Ashkenazi Jewish (ASJ) AF: 0.000514 AC: 13 AN: 25298

East Asian (EAS) AF: 0.00 AC: 0 AN: 36624

South Asian (SAS) AF: 0.00 AC: 0 AN: 80256

European-Finnish (FIN) AF: 0.000146 AC: 5 AN: 34326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00200 AC: 2171 AN: 1086924

Other (OTH) AF: 0.00180 AC: 105 AN: 58442

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74380

African (AFR) AF: 0.000265 AC: 11 AN: 41478

American (AMR) AF: 0.00170 AC: 26 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00179 AC: 122 AN: 67972

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.00114

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class I deficiency Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	17
DANN	Benign	0.59
PhyloP100		1.8
PromoterAI		0.098	Neutral
Mutation Taster		=91/9	polymorphism

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: rs148176741; hg19: chr6-32821582;