rs142455342

chr6-33305294-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_003190.5(TAPBP):c.563C>T(p.Thr188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,579,442 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T188A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: TAPBP NM_003190.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.218

Genes affected

TAPBP (HGNC:11566): (TAP binding protein) This gene encodes a transmembrane glycoprotein which mediates interaction between newly assembled major histocompatibility complex (MHC) class I molecules and the transporter associated with antigen processing (TAP), which is required for the transport of antigenic peptides across the endoplasmic reticulum membrane. This interaction is essential for optimal peptide loading on the MHC class I molecule. Up to four complexes of MHC class I and this protein may be bound to a single TAP molecule. This protein contains a C-terminal double-lysine motif (KKKAE) known to maintain membrane proteins in the endoplasmic reticulum. This gene lies within the major histocompatibility complex on chromosome 6. Alternative splicing results in three transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0045460463).
• BP6: Variant 6-33305294-G-A is Benign according to our data. Variant chr6-33305294-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 534737.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAPBP	NM_003190.5	c.563C>T	p.Thr188Ile	missense_variant	4/8	ENST00000434618.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAPBP	ENST00000434618.7	c.563C>T	p.Thr188Ile	missense_variant	4/8	1	NM_003190.5	P2

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000394 AC: 86 AN: 218052 Hom.: 0 AF XY: 0.000377 AC XY: 44 AN XY: 116824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000325

Gnomad ASJ exome AF: 0.00905

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.000768

GnomAD4 exome AF: 0.000231 AC: 329 AN: 1427174 Hom.: 1 Cov.: 34 AF XY: 0.000222 AC XY: 157 AN XY: 706536

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000465

Gnomad4 ASJ exome AF: 0.00870

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74438

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000480 Hom.: 1

Bravo AF: 0.000589

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000297 AC: 36

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.563C>T (p.T188I) alteration is located in exon 4 (coding exon 4) of the TAPBP gene. This alteration results from a C to T substitution at nucleotide position 563, causing the threonine (T) at amino acid position 188 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

MHC class I deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	11
Dann	Benign	0.97
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.69	T;T;T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.0045	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.81	N;N;N;N;N
REVEL	Benign	0.013
Sift	Benign	0.31	T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;.
Polyphen		0.0030	.;B;.;.;.
Vest4		0.097
MVP		0.25
MPC		0.39
ClinPred		0.015	T
GERP RS		0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.0
gMVP		0.29

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: rs142455342; hg19: chr6-33273071;