chr6-33304160-A-G

Variant names:

• chr6-33304160-A-G
• rs1768780166
• NM_003190.5:c.1268T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003190.5(TAPBP):​c.1268T>C​(p.Leu423Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TAPBP NM_003190.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84
• Publications: 0 publications found

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]

TAPBP Gene-Disease associations (from GenCC):

• MHC class I deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003190.5. 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
	TAPBP	NM_003190.5	MANE Select	c.1268T>C	p.Leu423Pro	missense	Exon 6 of 8	NP_003181.3
	TAPBP	NM_172208.3		c.1268T>C	p.Leu423Pro	missense	Exon 6 of 7	NP_757345.2	A0A0A0MSV9
	TAPBP	NM_001410875.1		c.1268T>C	p.Leu423Pro	missense	Exon 6 of 7	NP_001397804.1	A0A8V8TQC5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAPBP	ENST00000434618.7	TSL:1 MANE Select	c.1268T>C	p.Leu423Pro	missense	Exon 6 of 8	ENSP00000395701.2	O15533-1
	TAPBP	ENST00000426633.6	TSL:1	c.1268T>C	p.Leu423Pro	missense	Exon 6 of 7	ENSP00000404833.2	O15533-3
	TAPBP	ENST00000489157.6	TSL:1	c.1007T>C	p.Leu336Pro	missense	Exon 5 of 7	ENSP00000419659.1	O15533-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111988

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.49	T
PhyloP100		4.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.80
MutPred		0.67		Gain of sheet (P = 0.0101)
MVP		0.80
MPC		1.4
ClinPred		0.99	D
GERP RS		5.4
gMVP		0.88
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs1768780166; hg19: chr6-33271937;