6-32852088-T-C

Variant names:

• chr6-32852088-T-C
• rs2071481
• NM_000593.6:c.844+21A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000593.6(TAP1):​c.844+21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,612,612 control chromosomes in the GnomAD database, including 12,187 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 0.11 (1088 hom., cov: 31)
  • Exomes 𝑓: 0.12 (11099 hom.)
• Consequence: TAP1 NM_000593.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.279
• Publications: 37 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000593.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	NM_000593.6	MANE Select	c.844+21A>G		intron	N/A	NP_000584.3
	TAP1	NM_001292022.2		c.241+21A>G		intron	N/A	NP_001278951.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	ENST00000354258.5	TSL:1 MANE Select	c.844+21A>G		intron	N/A	ENSP00000346206.5
	TAP1	ENST00000698423.1		c.844+21A>G		intron	N/A	ENSP00000513711.1
	TAP1	ENST00000920268.1		c.844+21A>G		intron	N/A	ENSP00000590327.1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17325 AN: 151840 Hom.: 1076 Cov.: 31

Gnomad AFR AF: 0.0897

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0908

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.0976

GnomAD2 exomes AF: 0.138 AC: 33980 AN: 246266 AF XY: 0.140

Gnomad AFR exome AF: 0.0907

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.0644

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.117 AC: 171314 AN: 1460652 Hom.: 11099 Cov.: 34 AF XY: 0.120 AC XY: 87353 AN XY: 726660

African (AFR) AF: 0.0904 AC: 3026 AN: 33478

American (AMR) AF: 0.123 AC: 5490 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0630 AC: 1647 AN: 26136

East Asian (EAS) AF: 0.170 AC: 6731 AN: 39700

South Asian (SAS) AF: 0.210 AC: 18121 AN: 86256

European-Finnish (FIN) AF: 0.171 AC: 8914 AN: 52260

Middle Eastern (MID) AF: 0.169 AC: 977 AN: 5768

European-Non Finnish (NFE) AF: 0.108 AC: 119538 AN: 1111946

Other (OTH) AF: 0.114 AC: 6870 AN: 60386

GnomAD4 genome AF: 0.114 AC: 17364 AN: 151960 Hom.: 1088 Cov.: 31 AF XY: 0.118 AC XY: 8766 AN XY: 74272

African (AFR) AF: 0.0898 AC: 3720 AN: 41434

American (AMR) AF: 0.0918 AC: 1402 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 237 AN: 3470

East Asian (EAS) AF: 0.213 AC: 1097 AN: 5152

South Asian (SAS) AF: 0.213 AC: 1023 AN: 4810

European-Finnish (FIN) AF: 0.163 AC: 1723 AN: 10574

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7808 AN: 67950

Other (OTH) AF: 0.101 AC: 212 AN: 2102

Alfa AF: 0.114 Hom.: 4283

Bravo AF: 0.107

Asia WGS AF: 0.204 AC: 707 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.0
DANN	Benign	0.74
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2071481; hg19: chr6-32819865; COSMIC: COSV62754673; COSMIC: COSV62754673;