rs1057141

chr6-32850997-T-Cchr6-32850997-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000593.6(TAP1):c.997A>G(p.Ile333Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,612,592 control chromosomes in the GnomAD database, including 26,484 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3250 hom., cov: 31)
  • Exomes 𝑓: 0.17 (23234 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.18

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029444993).
• BP6: Variant 6-32850997-T-C is Benign according to our data. Variant chr6-32850997-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 13729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32850997-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP1	NM_000593.6	c.997A>G	p.Ile333Val	missense_variant	4/11	ENST00000354258.5
TAP1	NM_001292022.2	c.394A>G	p.Ile132Val	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP1	ENST00000354258.5	c.997A>G	p.Ile333Val	missense_variant	4/11	1	NM_000593.6	P1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30547 AN: 151824 Hom.: 3227 Cov.: 31

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.176

GnomAD3 exomes AF: 0.200 AC: 49398 AN: 246808 Hom.: 5284 AF XY: 0.200 AC XY: 26887 AN XY: 134488

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.229

Gnomad SAS exome AF: 0.276

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.174 AC: 253703 AN: 1460652 Hom.: 23234 Cov.: 36 AF XY: 0.177 AC XY: 128309 AN XY: 726626

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.183

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.171

Gnomad4 SAS exome AF: 0.276

Gnomad4 FIN exome AF: 0.207

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.202 AC: 30628 AN: 151940 Hom.: 3250 Cov.: 31 AF XY: 0.203 AC XY: 15111 AN XY: 74262

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.217

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.201

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.178

Alfa AF: 0.177 Hom.: 4380

Bravo AF: 0.200

TwinsUK AF: 0.163 AC: 604

ALSPAC AF: 0.157 AC: 604

ESP6500AA AF: 0.253 AC: 764

ESP6500EA AF: 0.165 AC: 891

ExAC AF: 0.203 AC: 23981

Asia WGS AF: 0.268 AC: 931 AN: 3478

EpiCase AF: 0.160

EpiControl AF: 0.159

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class I deficiency Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

PEPTIDE TRANSPORTER PSF1 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

May 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	1.3
Dann	Benign	0.73
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.37	N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.16
Sift	Benign	0.68	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.46
ClinPred		0.00087	T
GERP RS		-2.4
Varity_R		0.029
gMVP		0.58

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

Other links and lift over

dbSNP: rs1057141; hg19: chr6-32818774; COSMIC: COSV62754145; COSMIC: COSV62754145;