Genetic Variant TAPBP:p.Leu418Leu (chr6-33304174-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_003190.5(TAPBP):c.1254G>A(p.Leu418Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L418L) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TAPBP
NM_003190.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.202

Publications

0 publications found

Variant links:

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: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
MHC class I deficiency 1
Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

TAPBP links:

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new If you want to explore the variant's impact on the transcript NM_003190.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP7

Synonymous conserved (PhyloP=-0.202 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TAPBP	NM_003190.5	MANE Select	c.1254G>A	p.Leu418Leu	synonymous	Exon 6 of 8	NP_003181.3
TAPBP	NM_172208.3		c.1254G>A	p.Leu418Leu	synonymous	Exon 6 of 7	NP_757345.2	A0A0A0MSV9
TAPBP	NM_001410875.1		c.1254G>A	p.Leu418Leu	synonymous	Exon 6 of 7	NP_001397804.1	A0A8V8TQC5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TAPBP	ENST00000434618.7	TSL:1 MANE Select	c.1254G>A	p.Leu418Leu	synonymous	Exon 6 of 8	ENSP00000395701.2	O15533-1
TAPBP	ENST00000426633.6	TSL:1	c.1254G>A	p.Leu418Leu	synonymous	Exon 6 of 7	ENSP00000404833.2	O15533-3
TAPBP	ENST00000489157.6	TSL:1	c.993G>A	p.Leu331Leu	synonymous	Exon 5 of 7	ENSP00000419659.1	O15533-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727206

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.3

(source)

DANN

Benign

0.66

PhyloP100

-0.20

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over