rs142907576

Positions:

chr6-32853245-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_000593.6(TAP1):c.392T>C(p.Leu131Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,604,682 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 3 hom. )

Consequence

TAP1
NM_000593.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.03

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12755224).

BP6

Variant 6-32853245-A-G is Benign according to our data. Variant chr6-32853245-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 466388.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32853245-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00125 (191/152356) while in subpopulation NFE AF= 0.00256 (174/68016). AF 95% confidence interval is 0.00225. There are 1 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP1	NM_000593.6 linkuse as main transcript	c.392T>C	p.Leu131Pro	missense_variant	1/11	ENST00000354258.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP1	ENST00000354258.5 linkuse as main transcript	c.392T>C	p.Leu131Pro	missense_variant	1/11	1	NM_000593.6	P1	Q03518-1

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

191

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00111

AC:

252

AN:

226930

Hom.:

AF XY:

0.00102

AC XY:

126

AN XY:

123966

show subpopulations

Gnomad AFR exome

AF:

0.000529

Gnomad AMR exome

AF:

0.000307

Gnomad ASJ exome

AF:

0.000105

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000349

Gnomad FIN exome

AF:

0.000204

Gnomad NFE exome

AF:

0.00215

Gnomad OTH exome

AF:

0.000702

GnomAD4 exome

AF:

0.00182

AC:

2643

AN:

1452326

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

1210

AN XY:

721734

show subpopulations

Gnomad4 AFR exome

AF:

0.000450

Gnomad4 AMR exome

AF:

0.000253

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000470

Gnomad4 FIN exome

AF:

0.000193

Gnomad4 NFE exome

AF:

0.00225

Gnomad4 OTH exome

AF:

0.00130

GnomAD4 genome

AF:

0.00125

AC:

191

AN:

152356

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000264

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00256

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00177

Hom.:

Bravo

AF:

0.00123

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000993

AC:

ESP6500EA

AF:

0.00148

AC:

ExAC

AF:

0.000989

AC:

116

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MHC class I deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

Eigen

Benign

0.12

Eigen_PC

Benign

0.050

FATHMM_MKL

Benign

0.31

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.13

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.62

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.76

MVP

0.89

MPC

1.9

ClinPred

0.023

GERP RS

4.2

Varity_R

0.42

gMVP

0.76

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