12-6453067-A-G

Variant names:

• chr12-6453067-A-G
• NM_018009.5:c.65A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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

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]

ACMG classification

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018009.5. 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
	TAPBPL	NM_018009.5	MANE Select	c.65A>G	p.Lys22Arg	missense splice_region	Exon 2 of 7	NP_060479.3
	TAPBPL	NM_001351355.2		c.-326A>G		splice_region	Exon 3 of 8	NP_001338284.1
	TAPBPL	NM_001351355.2		c.-326A>G		5_prime_UTR	Exon 3 of 8	NP_001338284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAPBPL	ENST00000266556.8	TSL:1 MANE Select	c.65A>G	p.Lys22Arg	missense splice_region	Exon 2 of 7	ENSP00000266556.7	Q9BX59-1
	TAPBPL	ENST00000853206.1		c.65A>G	p.Lys22Arg	missense splice_region	Exon 2 of 8	ENSP00000523265.1
	TAPBPL	ENST00000954553.1		c.65A>G	p.Lys22Arg	missense splice_region	Exon 2 of 7	ENSP00000624612.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418648 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 701210

African (AFR) AF: 0.00 AC: 0 AN: 33070

American (AMR) AF: 0.00 AC: 0 AN: 36722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25250

East Asian (EAS) AF: 0.00 AC: 0 AN: 38314

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4810

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090418

Other (OTH) AF: 0.00 AC: 0 AN: 58836

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.7
DANN	Benign	0.83
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.47
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.037
Sift	Benign	0.060	T
Sift4G	Benign	0.49	T
Polyphen		0.0050	B
Vest4		0.097
MutPred		0.20		Loss of ubiquitination at K22 (P = 0.0092)
MVP		0.22
MPC		0.15
ClinPred		0.083	T
GERP RS		1.8
Varity_R		0.038
gMVP		0.20
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

hg19: chr12-6562233;