12-6453644-A-G

Variant names:

• chr12-6453644-A-G
• rs2532500
• NM_018009.5:c.493A>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.493A>G​(p.Thr165Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,613,272 control chromosomes in the GnomAD database, including 395,533 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T165I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.67 (34054 hom., cov: 32)
  • Exomes 𝑓: 0.70 (361479 hom.)
• Consequence: TAPBPL NM_018009.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.618
• Publications: 42 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=1.336663E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAPBPL	NM_018009.5	c.493A>G	p.Thr165Ala	missense_variant	Exon 3 of 7	ENST00000266556.8	NP_060479.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAPBPL	ENST00000266556.8	c.493A>G	p.Thr165Ala	missense_variant	Exon 3 of 7	1	NM_018009.5	ENSP00000266556.7

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101216 AN: 151954 Hom.: 34029 Cov.: 32

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.636

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.623

GnomAD2 exomes AF: 0.682 AC: 170695 AN: 250440 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: 1025482 AN: 1461200 Hom.: 361479 Cov.: 67 AF XY: 0.703 AC XY: 511166 AN XY: 726890

African (AFR) AF: 0.585 AC: 19596 AN: 33470

American (AMR) AF: 0.589 AC: 26312 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 14792 AN: 26116

East Asian (EAS) AF: 0.784 AC: 31137 AN: 39696

South Asian (SAS) AF: 0.760 AC: 65559 AN: 86230

European-Finnish (FIN) AF: 0.706 AC: 37655 AN: 53354

Middle Eastern (MID) AF: 0.571 AC: 3235 AN: 5666

European-Non Finnish (NFE) AF: 0.707 AC: 785976 AN: 1111660

Other (OTH) AF: 0.683 AC: 41220 AN: 60350

GnomAD4 genome AF: 0.666 AC: 101289 AN: 152072 Hom.: 34054 Cov.: 32 AF XY: 0.667 AC XY: 49577 AN XY: 74338

African (AFR) AF: 0.598 AC: 24789 AN: 41476

American (AMR) AF: 0.635 AC: 9709 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1976 AN: 3460

East Asian (EAS) AF: 0.777 AC: 4011 AN: 5164

South Asian (SAS) AF: 0.763 AC: 3683 AN: 4830

European-Finnish (FIN) AF: 0.705 AC: 7441 AN: 10552

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.700 AC: 47589 AN: 67988

Other (OTH) AF: 0.628 AC: 1327 AN: 2114

Alfa AF: 0.681 Hom.: 98202

Bravo AF: 0.651

TwinsUK AF: 0.700 AC: 2594

ALSPAC AF: 0.716 AC: 2758

ESP6500AA AF: 0.587 AC: 2585

ESP6500EA AF: 0.692 AC: 5954

ExAC AF: 0.682 AC: 82821

EpiCase AF: 0.678

EpiControl AF: 0.679

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.60
DANN	Benign	0.25
DEOGEN2	Benign	0.0022	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.20	T;T
MetaRNN	Benign	0.0000013	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	.;N
PhyloP100		0.62
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.97	N;N
REVEL	Benign	0.029
Sift	Benign	0.87	T;T
Sift4G	Benign	0.79	T;T
Vest4		0.0070
ClinPred		0.00081	T
GERP RS		1.7
Varity_R		0.028
gMVP		0.13
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

dbSNP: rs2532500; hg19: chr12-6562810; COSMIC: COSV56945960; COSMIC: COSV56945960;