rs2228106

chr6-32848671-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000593.6(TAP1):c.1547C>T(p.Pro516Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,614,104 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (17 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.52

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011913836).
• BP6: Variant 6-32848671-G-A is Benign according to our data. Variant chr6-32848671-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 534714.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr6-32848671-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00267 (407/152286) while in subpopulation NFE AF= 0.00447 (304/68016). AF 95% confidence interval is 0.00406. There are 0 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP1	NM_000593.6	c.1547C>T	p.Pro516Leu	missense_variant	7/11	ENST00000354258.5
TAP1	NM_001292022.2	c.944C>T	p.Pro315Leu	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP1	ENST00000354258.5	c.1547C>T	p.Pro516Leu	missense_variant	7/11	1	NM_000593.6	P1

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00233 AC: 585 AN: 251496 Hom.: 1 AF XY: 0.00241 AC XY: 328 AN XY: 135922

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00380

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00382 AC: 5584 AN: 1461818 Hom.: 17 Cov.: 34 AF XY: 0.00383 AC XY: 2784 AN XY: 727200

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000846

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.00462

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00267 AC: 407 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74472

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00378 Hom.: 3

Bravo AF: 0.00270

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00227 AC: 275

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 02, 2019

- -

MHC class I deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

TAP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.037
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.50	N
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.95	D;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.18
MVP		0.90
MPC		0.61
ClinPred		0.11	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.52

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: rs2228106; hg19: chr6-32816448;