12-6453677-A-C

Position:

• chr12-6453677-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018009.5(TAPBPL):​c.526A>C​(p.Asn176His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TAPBPL NM_018009.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21135777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAPBPL	NM_018009.5	c.526A>C	p.Asn176His	missense_variant	3/7	ENST00000266556.8	NP_060479.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAPBPL	ENST00000266556.8	c.526A>C	p.Asn176His	missense_variant	3/7	1	NM_018009.5	ENSP00000266556	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfanoid habitus and intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T;T
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.7	.;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.8	D;N
REVEL	Benign	0.064
Sift	Benign	0.080	T;T
Sift4G	Benign	0.093	T;T
Polyphen		0.98	.;D
Vest4		0.12
MutPred		0.29		.;Gain of catalytic residue at L175 (P = 0.0017);
MVP		0.59
MPC		0.20
ClinPred		0.35	T
GERP RS		1.6
Varity_R		0.16
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1592129355; hg19: chr12-6562843;