rs1057149

chr6-32847165-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000593.6(TAP1):c.1943G>A(p.Arg648Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 1,612,612 control chromosomes in the GnomAD database, including 1,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.057 (481 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1055 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.791

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004969448).
• BP6: Variant 6-32847165-C-T is Benign according to our data. Variant chr6-32847165-C-T is described in ClinVar as [Benign]. Clinvar id is 466383.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32847165-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP1	NM_000593.6	c.1943G>A	p.Arg648Gln	missense_variant	10/11	ENST00000354258.5
TAP1	NM_001292022.2	c.1340G>A	p.Arg447Gln	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP1	ENST00000354258.5	c.1943G>A	p.Arg648Gln	missense_variant	10/11	1	NM_000593.6	P1

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8598 AN: 152150 Hom.: 471 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0538

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0608

GnomAD3 exomes AF: 0.0309 AC: 7588 AN: 245630 Hom.: 291 AF XY: 0.0270 AC XY: 3612 AN XY: 133964

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.0444

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.00382

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0411

GnomAD4 exome AF: 0.0256 AC: 37443 AN: 1460344 Hom.: 1055 Cov.: 32 AF XY: 0.0246 AC XY: 17842 AN XY: 726528

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.0463

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.000680

Gnomad4 SAS exome AF: 0.00431

Gnomad4 FIN exome AF: 0.00231

Gnomad4 NFE exome AF: 0.0217

Gnomad4 OTH exome AF: 0.0412

GnomAD4 genome AF: 0.0567 AC: 8639 AN: 152268 Hom.: 481 Cov.: 32 AF XY: 0.0542 AC XY: 4039 AN XY: 74454

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0537

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.0222

Gnomad4 OTH AF: 0.0601

Alfa AF: 0.0357 Hom.: 235

Bravo AF: 0.0648

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.123 AC: 373

ESP6500EA AF: 0.0292 AC: 158

ExAC AF: 0.0301 AC: 3593

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class I deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.68	D
MetaRNN	Benign	0.0050	T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.2e-15	P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		1.0	D;.
Vest4		0.15
MPC		1.6
ClinPred		0.036	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057149; hg19: chr6-32814942; COSMIC: COSV99059097; COSMIC: COSV99059097;