Genetic Variant TAPBPL:p.Lys22Arg (chr12-6453067-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018009.5(TAPBPL):c.65A>G(p.Lys22Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TAPBPL
NM_018009.5 missense, splice_region

Scores

Splicing: ADA: 0.0001138

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.468

Publications

0 publications found

Variant links:

Genes affected

TAPBPL (HGNC:30683): (TAP binding protein like) Tapasin, or TAPBP (MIM 601962), is a member of the variable-constant Ig superfamily that links major histocompatibility complex (MHC) class I molecules to the transporter associated with antigen processing (TAP; see MIM 170260) in the endoplasmic reticulum (ER). The TAPBP gene is located near the MHC complex on chromosome 6p21.3. TAPBPL is a member of the Ig superfamily that is localized on chromosome 12p13.3, a region somewhat paralogous to the MHC.[supplied by OMIM, Mar 2008]

TAPBPL links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06322718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAPBPL	NM_018009.5 link	c.65A>G	p.Lys22Arg	missense_variant, splice_region_variant	Exon 2 of 7	ENST00000266556.8	NP_060479.3	Q9BX59-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAPBPL	ENST00000266556.8 link	c.65A>G	p.Lys22Arg	missense_variant, splice_region_variant	Exon 2 of 7	1	NM_018009.5	ENSP00000266556.7		Q9BX59-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1418648

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

701210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33070

American (AMR)

AF:

0.00

AC:

AN:

36722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25250

East Asian (EAS)

AF:

0.00

AC:

AN:

38314

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4810

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090418

Other (OTH)

AF:

0.00

AC:

AN:

58836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.65A>G (p.K22R) alteration is located in exon 2 (coding exon 2) of the TAPBPL gene. This alteration results from a A to G substitution at nucleotide position 65, causing the lysine (K) at amino acid position 22 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.7

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.0054

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.38

M_CAP

Benign

0.0061

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

PhyloP100

0.47

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.41

REVEL

Benign

0.037

Sift

Benign

0.060

Sift4G

Benign

0.49

Polyphen

0.0050

Vest4

0.097

MutPred

0.20

Loss of ubiquitination at K22 (P = 0.0092);

MVP

0.22

MPC

0.15

ClinPred

0.083

GERP RS

1.8

Varity_R

0.038

gMVP

0.20

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.0040

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over