6-32847125-C-T

Variant names:

• chr6-32847125-C-T
• rs41551515
• NM_000593.6:c.1983G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_000593.6(TAP1):​c.1983G>A​(p.Pro661Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 1,612,922 control chromosomes in the GnomAD database, including 792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (68 hom., cov: 32)
  • Exomes 𝑓: 0.029 (724 hom.)
• Consequence: TAP1 NM_000593.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.681
• Publications: 11 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 6-32847125-C-T is Benign according to our data. Variant chr6-32847125-C-T is described in ClinVar as Benign. ClinVar VariationId is 466384.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.681 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0283 (4310/152312) while in subpopulation SAS AF = 0.034 (164/4826). AF 95% confidence interval is 0.0312. There are 68 homozygotes in GnomAd4. There are 2124 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 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.1983G>A	p.Pro661Pro	synonymous	Exon 10 of 11	NP_000584.3
	TAP1	NM_001292022.2		c.1380G>A	p.Pro460Pro	synonymous	Exon 10 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.1983G>A	p.Pro661Pro	synonymous	Exon 10 of 11	ENSP00000346206.5	Q03518-1
	TAP1	ENST00000698423.1		c.1983G>A	p.Pro661Pro	synonymous	Exon 10 of 12	ENSP00000513711.1	A0A8V8TM76
	TAP1	ENST00000920268.1		c.1995G>A	p.Pro665Pro	synonymous	Exon 10 of 11	ENSP00000590327.1

Frequencies

GnomAD3 genomes AF: 0.0283 AC: 4307 AN: 152194 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0335

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.0277 AC: 6822 AN: 246340 AF XY: 0.0284

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.000602

Gnomad FIN exome AF: 0.0353

Gnomad NFE exome AF: 0.0340

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0291 AC: 42509 AN: 1460610 Hom.: 724 Cov.: 32 AF XY: 0.0295 AC XY: 21440 AN XY: 726620

African (AFR) AF: 0.0308 AC: 1031 AN: 33480

American (AMR) AF: 0.0138 AC: 615 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 281 AN: 26136

East Asian (EAS) AF: 0.000554 AC: 22 AN: 39700

South Asian (SAS) AF: 0.0374 AC: 3230 AN: 86258

European-Finnish (FIN) AF: 0.0341 AC: 1777 AN: 52152

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.0306 AC: 33974 AN: 1112010

Other (OTH) AF: 0.0255 AC: 1541 AN: 60382

GnomAD4 genome AF: 0.0283 AC: 4310 AN: 152312 Hom.: 68 Cov.: 32 AF XY: 0.0285 AC XY: 2124 AN XY: 74458

African (AFR) AF: 0.0286 AC: 1190 AN: 41562

American (AMR) AF: 0.0150 AC: 230 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5184

South Asian (SAS) AF: 0.0340 AC: 164 AN: 4826

European-Finnish (FIN) AF: 0.0359 AC: 381 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0323 AC: 2196 AN: 68036

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.0301 Hom.: 238

Bravo AF: 0.0262

Asia WGS AF: 0.0290 AC: 103 AN: 3478

EpiCase AF: 0.0303

EpiControl AF: 0.0290

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	MHC class I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	10
DANN	Benign	0.87
PhyloP100		-0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs41551515; hg19: chr6-32814902;