rs41550019

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000593.6(TAP1):c.1372G>T(p.Val458Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,612,284 control chromosomes in the GnomAD database, including 1,523 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.057 ( 472 hom., cov: 32)

Exomes 𝑓: 0.026 ( 1051 hom. )

Consequence

TAP1
NM_000593.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.131

Variant links:

Genes affected

TAP1 (HGNC:43): (transporter 1, ATP binding cassette subfamily B member) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is involved in the pumping of degraded cytosolic peptides across the endoplasmic reticulum into the membrane-bound compartment where class I molecules assemble. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

TAP1 links:

PSMB9 (HGNC:9546): (proteasome 20S subunit beta 9) The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 1 (proteasome beta 6 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. [provided by RefSeq, Mar 2010]

PSMB9 links:

TAP1 (HGNC:):

TAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039856136).

BP6

Variant 6-32848995-C-A is Benign according to our data. Variant chr6-32848995-C-A is described in ClinVar as [Benign]. Clinvar id is 466381.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32848995-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAP1	NM_000593.6 linkuse as main transcript	c.1372G>T	p.Val458Leu	missense_variant	6/11	ENST00000354258.5	NP_000584.3	Q03518-1A0A0S2Z5A6X5CKB3
TAP1	NM_001292022.2 linkuse as main transcript	c.769G>T	p.Val257Leu	missense_variant	6/11		NP_001278951.1	Q03518B7Z7P4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAP1	ENST00000354258.5 linkuse as main transcript	c.1372G>T	p.Val458Leu	missense_variant	6/11	1	NM_000593.6	ENSP00000346206.5		Q03518-1

Frequencies

GnomAD3 genomes

AF:

0.0566

AC:

8605

AN:

152118

Hom.:

464

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0537

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0223

Gnomad OTH

AF:

0.0602

GnomAD3 exomes

AF:

0.0308

AC:

7554

AN:

244888

Hom.:

283

AF XY:

0.0268

AC XY:

3545

AN XY:

132492

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.0440

Gnomad ASJ exome

AF:

0.126

Gnomad EAS exome

AF:

0.00122

Gnomad SAS exome

AF:

0.00369

Gnomad FIN exome

AF:

0.00215

Gnomad NFE exome

AF:

0.0209

Gnomad OTH exome

AF:

0.0407

GnomAD4 exome

AF:

0.0256

AC:

37376

AN:

1460048

Hom.:

1051

Cov.:

AF XY:

0.0245

AC XY:

17815

AN XY:

726168

show subpopulations

Gnomad4 AFR exome

AF:

0.139

Gnomad4 AMR exome

AF:

0.0461

Gnomad4 ASJ exome

AF:

0.125

Gnomad4 EAS exome

AF:

0.000681

Gnomad4 SAS exome

AF:

0.00430

Gnomad4 FIN exome

AF:

0.00227

Gnomad4 NFE exome

AF:

0.0217

Gnomad4 OTH exome

AF:

0.0412

GnomAD4 genome

AF:

0.0568

AC:

8644

AN:

152236

Hom.:

472

Cov.:

AF XY:

0.0544

AC XY:

4052

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.137

Gnomad4 AMR

AF:

0.0536

Gnomad4 ASJ

AF:

0.130

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.0223

Gnomad4 OTH

AF:

0.0595

Alfa

AF:

0.0338

Hom.:

226

Bravo

AF:

0.0650

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.124

AC:

376

ESP6500EA

AF:

0.0292

AC:

158

ExAC

AF:

0.0305

AC:

3696

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MHC class I deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.66

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.33

Sift

Benign

0.24

Sift4G

Benign

0.17

Polyphen

0.40

Vest4

0.12

MutPred

0.34

Gain of sheet (P = 0.0166);

MPC

0.98

ClinPred

0.015

GERP RS

4.0

Varity_R

0.095

gMVP

0.66

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over