rs36229525

Variant names:

• chr6-32852223-C-A
• rs36229525
• NM_000593.6:c.730G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32852223-C-A
• chr6-32852223-C-T

Variant summary

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

The NM_000593.6(TAP1):​c.730G>T​(p.Val244Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,612,922 control chromosomes in the GnomAD database, including 34 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (22 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -5.85
• Publications: 9 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 (MetaRNN=0.007103294).
• BP6: Variant 6-32852223-C-A is Benign according to our data. Variant chr6-32852223-C-A is described in ClinVar as Benign. ClinVar VariationId is 466391.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00743 (1131/152140) while in subpopulation AFR AF = 0.0169 (702/41500). AF 95% confidence interval is 0.0159. There are 12 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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.730G>T	p.Val244Leu	missense	Exon 3 of 11	NP_000584.3
	TAP1	NM_001292022.2		c.127G>T	p.Val43Leu	missense	Exon 3 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.730G>T	p.Val244Leu	missense	Exon 3 of 11	ENSP00000346206.5	Q03518-1
	TAP1	ENST00000698423.1		c.730G>T	p.Val244Leu	missense	Exon 3 of 12	ENSP00000513711.1	A0A8V8TM76
	TAP1	ENST00000920268.1		c.730G>T	p.Val244Leu	missense	Exon 3 of 11	ENSP00000590327.1

Frequencies

GnomAD3 genomes AF: 0.00744 AC: 1131 AN: 152022 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00441 AC: 1088 AN: 246702 AF XY: 0.00396

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.00751

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00250

Gnomad OTH exome AF: 0.00740

GnomAD4 exome AF: 0.00321 AC: 4696 AN: 1460782 Hom.: 22 Cov.: 34 AF XY: 0.00305 AC XY: 2218 AN XY: 726700

African (AFR) AF: 0.0162 AC: 541 AN: 33480

American (AMR) AF: 0.00823 AC: 368 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 561 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.0000764 AC: 4 AN: 52330

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.00258 AC: 2869 AN: 1112002

Other (OTH) AF: 0.00522 AC: 315 AN: 60384

GnomAD4 genome AF: 0.00743 AC: 1131 AN: 152140 Hom.: 12 Cov.: 32 AF XY: 0.00718 AC XY: 534 AN XY: 74378

African (AFR) AF: 0.0169 AC: 702 AN: 41500

American (AMR) AF: 0.0103 AC: 158 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00254 AC: 173 AN: 68006

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00473 Hom.: 17

Bravo AF: 0.00906

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0156 AC: 47

ESP6500EA AF: 0.00351 AC: 19

ExAC AF: 0.00432 AC: 511

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00344

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	MHC class I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.0010
DANN	Benign	0.67
DEOGEN2	Benign	0.11	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.056	N
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.035	N
PhyloP100		-5.8
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.25
Sift	Benign	0.85	T
Sift4G	Benign	0.43	T
Polyphen		0.011	B
Vest4		0.24
MutPred		0.25		Gain of catalytic residue at V304 (P = 0.2142)
MVP		0.51
MPC		0.58
ClinPred		0.012	T
GERP RS		-9.6
Varity_R		0.066
gMVP		0.73
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: rs36229525; hg19: chr6-32820000; COSMIC: COSV100841361; COSMIC: COSV100841361;