chr6-32847198-T-C

Variant names:

• chr6-32847198-T-C
• rs1135216
• NM_000593.6:c.1910A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000593.6(TAP1):​c.1910A>G​(p.Asp637Gly) variant causes a missense change. The variant allele was found at a frequency of 0.149 in 1,611,520 control chromosomes in the GnomAD database, including 18,910 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D637D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2418 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16492 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.48
• Publications: 96 publications found

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]

PSMB9 Gene-Disease associations (from GenCC):

• proteasome-associated autoinflammatory syndrome 3

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020890832).
• BP6: Variant 6-32847198-T-C is Benign according to our data. Variant chr6-32847198-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000593.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	NM_000593.6	MANE Select	c.1910A>G	p.Asp637Gly	missense	Exon 10 of 11	NP_000584.3
	TAP1	NM_001292022.2		c.1307A>G	p.Asp436Gly	missense	Exon 10 of 11	NP_001278951.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	ENST00000354258.5	TSL:1 MANE Select	c.1910A>G	p.Asp637Gly	missense	Exon 10 of 11	ENSP00000346206.5
	TAP1	ENST00000698423.1		c.1910A>G	p.Asp637Gly	missense	Exon 10 of 12	ENSP00000513711.1
	TAP1	ENST00000698424.1		c.1781A>G	p.Asp594Gly	missense	Exon 9 of 10	ENSP00000513712.1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26544 AN: 152066 Hom.: 2401 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.170 AC: 41650 AN: 244650 AF XY: 0.168

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.159

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.147 AC: 213920 AN: 1459336 Hom.: 16492 Cov.: 33 AF XY: 0.149 AC XY: 107911 AN XY: 726094

African (AFR) AF: 0.237 AC: 7947 AN: 33474

American (AMR) AF: 0.181 AC: 8107 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 4110 AN: 26132

East Asian (EAS) AF: 0.135 AC: 5351 AN: 39698

South Asian (SAS) AF: 0.218 AC: 18782 AN: 86258

European-Finnish (FIN) AF: 0.178 AC: 9056 AN: 50972

Middle Eastern (MID) AF: 0.192 AC: 1105 AN: 5768

European-Non Finnish (NFE) AF: 0.135 AC: 150233 AN: 1111948

Other (OTH) AF: 0.153 AC: 9229 AN: 60372

GnomAD4 genome AF: 0.175 AC: 26615 AN: 152184 Hom.: 2418 Cov.: 32 AF XY: 0.175 AC XY: 13049 AN XY: 74400

African (AFR) AF: 0.232 AC: 9637 AN: 41504

American (AMR) AF: 0.150 AC: 2289 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3466

East Asian (EAS) AF: 0.156 AC: 805 AN: 5176

South Asian (SAS) AF: 0.205 AC: 989 AN: 4822

European-Finnish (FIN) AF: 0.177 AC: 1875 AN: 10602

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9895 AN: 67994

Other (OTH) AF: 0.159 AC: 336 AN: 2116

Alfa AF: 0.155 Hom.: 4903

Bravo AF: 0.175

TwinsUK AF: 0.138 AC: 511

ALSPAC AF: 0.133 AC: 514

ESP6500AA AF: 0.223 AC: 672

ESP6500EA AF: 0.141 AC: 762

ExAC AF: 0.171 AC: 20419

Asia WGS AF: 0.197 AC: 685 AN: 3478

EpiCase AF: 0.138

EpiControl AF: 0.137

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

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 01, 1992

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N
PhyloP100		5.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	5.8	N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.095
MPC		0.73
ClinPred		0.012	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.61
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1135216; hg19: chr6-32814975; COSMIC: COSV62754137; COSMIC: COSV62754137;