12-6453587-A-G

Variant names:

• chr12-6453587-A-G
• rs2532501
• NM_018009.5:c.436A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018009.5(TAPBPL):​c.436A>G​(p.Met146Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.699 in 1,613,902 control chromosomes in the GnomAD database, including 395,884 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.67 (34091 hom., cov: 32)
  • Exomes 𝑓: 0.70 (361793 hom.)
• Consequence: TAPBPL NM_018009.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.272
• Publications: 51 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.384362E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAPBPL	NM_018009.5	MANE Select	c.436A>G	p.Met146Val	missense	Exon 3 of 7	NP_060479.3
	TAPBPL	NM_001351355.2		c.46A>G	p.Met16Val	missense	Exon 4 of 8	NP_001338284.1
	TAPBPL	NR_147126.2		n.508A>G		non_coding_transcript_exon	Exon 3 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAPBPL	ENST00000266556.8	TSL:1 MANE Select	c.436A>G	p.Met146Val	missense	Exon 3 of 7	ENSP00000266556.7
	TAPBPL	ENST00000544021.5	TSL:3	c.205A>G	p.Met69Val	missense	Exon 2 of 5	ENSP00000445341.1
	TAPBPL	ENST00000539384.5	TSL:5	n.467A>G		non_coding_transcript_exon	Exon 3 of 7

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101265 AN: 151946 Hom.: 34066 Cov.: 32

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.623

GnomAD2 exomes AF: 0.682 AC: 171357 AN: 251262 AF XY: 0.688

Gnomad AFR exome AF: 0.596

Gnomad AMR exome AF: 0.586

Gnomad ASJ exome AF: 0.571

Gnomad EAS exome AF: 0.772

Gnomad FIN exome AF: 0.707

Gnomad NFE exome AF: 0.693

Gnomad OTH exome AF: 0.664

GnomAD4 exome AF: 0.702 AC: 1026143 AN: 1461838 Hom.: 361793 Cov.: 78 AF XY: 0.703 AC XY: 511517 AN XY: 727214

African (AFR) AF: 0.585 AC: 19601 AN: 33478

American (AMR) AF: 0.590 AC: 26370 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 14804 AN: 26136

East Asian (EAS) AF: 0.784 AC: 31143 AN: 39700

South Asian (SAS) AF: 0.760 AC: 65582 AN: 86256

European-Finnish (FIN) AF: 0.706 AC: 37691 AN: 53404

Middle Eastern (MID) AF: 0.572 AC: 3301 AN: 5768

European-Non Finnish (NFE) AF: 0.707 AC: 786400 AN: 1111984

Other (OTH) AF: 0.683 AC: 41251 AN: 60392

GnomAD4 genome AF: 0.666 AC: 101338 AN: 152064 Hom.: 34091 Cov.: 32 AF XY: 0.667 AC XY: 49613 AN XY: 74340

African (AFR) AF: 0.598 AC: 24782 AN: 41456

American (AMR) AF: 0.636 AC: 9711 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1978 AN: 3468

East Asian (EAS) AF: 0.777 AC: 4018 AN: 5172

South Asian (SAS) AF: 0.763 AC: 3687 AN: 4830

European-Finnish (FIN) AF: 0.705 AC: 7450 AN: 10562

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47623 AN: 67996

Other (OTH) AF: 0.627 AC: 1322 AN: 2108

Alfa AF: 0.680 Hom.: 132154

Bravo AF: 0.651

TwinsUK AF: 0.700 AC: 2594

ALSPAC AF: 0.715 AC: 2757

ESP6500AA AF: 0.586 AC: 2584

ESP6500EA AF: 0.692 AC: 5954

ExAC AF: 0.683 AC: 82908

Asia WGS AF: 0.740 AC: 2570 AN: 3478

EpiCase AF: 0.679

EpiControl AF: 0.679

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.90
DANN	Benign	0.59
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	6.4e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.92	N
PhyloP100		-0.27
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.012
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0080
MPC		0.18
ClinPred		0.0016	T
GERP RS		-4.2
Varity_R		0.047
gMVP		0.23
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2532501; hg19: chr12-6562753; COSMIC: COSV56946983; COSMIC: COSV56946983;