rs56366814

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000593.6(TAP1):c.1051-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,610,784 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 18 hom. )

Consequence

TAP1
NM_000593.6 splice_region, intron

Scores

Splicing: ADA: 0.002864

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.896

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 6-32850520-G-A is Benign according to our data. Variant chr6-32850520-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 534731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32850520-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00289 (440/152358) while in subpopulation AMR AF= 0.00627 (96/15312). AF 95% confidence interval is 0.00526. There are 6 homozygotes in gnomad4. There are 222 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAP1	NM_000593.6 link	c.1051-3C>T		splice_region_variant, intron_variant		ENST00000354258.5	NP_000584.3	Q03518-1A0A0S2Z5A6X5CKB3
TAP1	NM_001292022.2 link	c.448-3C>T		splice_region_variant, intron_variant			NP_001278951.1	Q03518B7Z7P4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAP1	ENST00000354258.5 link	c.1051-3C>T		splice_region_variant, intron_variant		1	NM_000593.6	ENSP00000346206.5		Q03518-1

Frequencies

GnomAD3 genomes

AF:

0.00288

AC:

439

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00628

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00260

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00399

AC:

993

AN:

248714

Hom.:

AF XY:

0.00415

AC XY:

559

AN XY:

134726

show subpopulations

Gnomad AFR exome

AF:

0.000372

Gnomad AMR exome

AF:

0.00426

Gnomad ASJ exome

AF:

0.0308

Gnomad EAS exome

AF:

0.000926

Gnomad SAS exome

AF:

0.00415

Gnomad FIN exome

AF:

0.000722

Gnomad NFE exome

AF:

0.00299

Gnomad OTH exome

AF:

0.00540

GnomAD4 exome

AF:

0.00308

AC:

4493

AN:

1458426

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

2274

AN XY:

725672

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00418

Gnomad4 ASJ exome

AF:

0.0298

Gnomad4 EAS exome

AF:

0.000781

Gnomad4 SAS exome

AF:

0.00348

Gnomad4 FIN exome

AF:

0.000950

Gnomad4 NFE exome

AF:

0.00253

Gnomad4 OTH exome

AF:

0.00428

GnomAD4 genome

AF:

0.00289

AC:

440

AN:

152358

Hom.:

Cov.:

AF XY:

0.00298

AC XY:

222

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.00627

Gnomad4 ASJ

AF:

0.0311

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.00260

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00583

Hom.:

Bravo

AF:

0.00308

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00376

EpiControl

AF:

0.00427

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TAP1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

MHC class I deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0029

dbscSNV1_RF

Benign

0.32

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

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