6-32850997-T-C

Variant names:

• chr6-32850997-T-C
• rs1057141
• NM_000593.6:c.997A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000593.6(TAP1):​c.997A>G​(p.Ile333Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,612,592 control chromosomes in the GnomAD database, including 26,484 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3250 hom., cov: 31)
  • Exomes 𝑓: 0.17 (23234 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.18
• Publications: 69 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029444993).
• BP6: Variant 6-32850997-T-C is Benign according to our data. Variant chr6-32850997-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.257 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.997A>G	p.Ile333Val	missense	Exon 4 of 11	NP_000584.3
	TAP1	NM_001292022.2		c.394A>G	p.Ile132Val	missense	Exon 4 of 11	NP_001278951.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	ENST00000354258.5	TSL:1 MANE Select	c.997A>G	p.Ile333Val	missense	Exon 4 of 11	ENSP00000346206.5	Q03518-1
	TAP1	ENST00000698423.1		c.997A>G	p.Ile333Val	missense	Exon 4 of 12	ENSP00000513711.1	A0A8V8TM76
	TAP1	ENST00000920268.1		c.997A>G	p.Ile333Val	missense	Exon 4 of 11	ENSP00000590327.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30547 AN: 151824 Hom.: 3227 Cov.: 31

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.176

GnomAD2 exomes AF: 0.200 AC: 49398 AN: 246808 AF XY: 0.200

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.229

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.174 AC: 253703 AN: 1460652 Hom.: 23234 Cov.: 36 AF XY: 0.177 AC XY: 128309 AN XY: 726626

African (AFR) AF: 0.266 AC: 8888 AN: 33476

American (AMR) AF: 0.183 AC: 8185 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5199 AN: 26136

East Asian (EAS) AF: 0.171 AC: 6784 AN: 39696

South Asian (SAS) AF: 0.276 AC: 23794 AN: 86258

European-Finnish (FIN) AF: 0.207 AC: 10853 AN: 52318

Middle Eastern (MID) AF: 0.221 AC: 1272 AN: 5750

European-Non Finnish (NFE) AF: 0.160 AC: 177728 AN: 1111914

Other (OTH) AF: 0.182 AC: 11000 AN: 60380

GnomAD4 genome AF: 0.202 AC: 30628 AN: 151940 Hom.: 3250 Cov.: 31 AF XY: 0.203 AC XY: 15111 AN XY: 74262

African (AFR) AF: 0.261 AC: 10800 AN: 41412

American (AMR) AF: 0.161 AC: 2460 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 718 AN: 3466

East Asian (EAS) AF: 0.217 AC: 1117 AN: 5154

South Asian (SAS) AF: 0.269 AC: 1293 AN: 4812

European-Finnish (FIN) AF: 0.201 AC: 2120 AN: 10560

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11516 AN: 67950

Other (OTH) AF: 0.178 AC: 375 AN: 2102

Alfa AF: 0.181 Hom.: 6420

Bravo AF: 0.200

TwinsUK AF: 0.163 AC: 604

ALSPAC AF: 0.157 AC: 604

ESP6500AA AF: 0.253 AC: 764

ESP6500EA AF: 0.165 AC: 891

ExAC AF: 0.203 AC: 23981

Asia WGS AF: 0.268 AC: 931 AN: 3478

EpiCase AF: 0.160

EpiControl AF: 0.159

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	MHC class I deficiency (3)
-	-	1	not specified (1)
-	-	1	PEPTIDE TRANSPORTER PSF1 POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.3
DANN	Benign	0.73
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.37	N
PhyloP100		-1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.16
Sift	Benign	0.68	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.46
ClinPred		0.00087	T
GERP RS		-2.4
Varity_R		0.029
gMVP		0.58
Mutation Taster		=98/2	polymorphism (auto)

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: rs1057141; hg19: chr6-32818774; COSMIC: COSV62754145; COSMIC: COSV62754145;