rs121917702

Positions:

• chr6-32847132-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000593.6(TAP1):​c.1976G>A​(p.Arg659Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,612,946 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R659W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 U:2 B:2
• Conservation: PhyloP100: 5.42

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060657978).
• BP6: Variant 6-32847132-C-T is Benign according to our data. Variant chr6-32847132-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 13731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000919 (140/152326) while in subpopulation NFE AF= 0.00169 (115/68038). AF 95% confidence interval is 0.00144. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP1	NM_000593.6	c.1976G>A	p.Arg659Gln	missense_variant	10/11	ENST00000354258.5
TAP1	NM_001292022.2	c.1373G>A	p.Arg458Gln	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP1	ENST00000354258.5	c.1976G>A	p.Arg659Gln	missense_variant	10/11	1	NM_000593.6	P1

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00120 AC: 295 AN: 246260 Hom.: 1 AF XY: 0.00118 AC XY: 158 AN XY: 134250

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000988

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.00156 AC: 2282 AN: 1460620 Hom.: 2 Cov.: 32 AF XY: 0.00151 AC XY: 1096 AN XY: 726630

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00117

Gnomad4 NFE exome AF: 0.00192

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74494

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00158 Hom.: 3

Bravo AF: 0.000873

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00111 AC: 6

ExAC AF: 0.00155 AC: 185

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:2 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

MHC class I deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 02, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

TAP1 deficiency, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0060	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.061	T;T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	0.88	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.0050	D;.
Polyphen		1.0	D;.
Vest4		0.85
MVP		0.85
MPC		1.6
ClinPred		0.12	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs121917702; hg19: chr6-32814909;