rs1135216

chr6-32847198-T-Cchr6-32847198-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.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. 11/19 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

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=0.0020890832).
• BP6: Variant 6-32847198-T-C is Benign according to our data. Variant chr6-32847198-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 13730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32847198-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP1	NM_000593.6	c.1910A>G	p.Asp637Gly	missense_variant	10/11	ENST00000354258.5
TAP1	NM_001292022.2	c.1307A>G	p.Asp436Gly	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP1	ENST00000354258.5	c.1910A>G	p.Asp637Gly	missense_variant	10/11	1	NM_000593.6	P1

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

GnomAD3 exomes AF: 0.170 AC: 41650 AN: 244650 Hom.: 3749 AF XY: 0.168 AC XY: 22478 AN XY: 133578

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 SAS exome AF: 0.218

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

Gnomad4 AFR exome AF: 0.237

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.135

Gnomad4 SAS exome AF: 0.218

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.153

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

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.159

Alfa AF: 0.150 Hom.: 2794

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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	- -

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	0.048
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
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;.
MutationTaster	Benign	1.4e-36	P;P;P
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

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

Publications

LitVar

Other links and lift over

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