rs2228110

Variant names:

• chr6-32849112-C-A
• rs2228110
• NM_000593.6:c.1255G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32849112-C-A
• chr6-32849112-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000593.6(TAP1):​c.1255G>T​(p.Gly419Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,581,108 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G419S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (89 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (87 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.39
• Publications: 8 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059488714).
• BP6: Variant 6-32849112-C-A is Benign according to our data. Variant chr6-32849112-C-A is described in ClinVar as Benign. ClinVar VariationId is 466380.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0617 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.1255G>T	p.Gly419Cys	missense	Exon 6 of 11	NP_000584.3
	TAP1	NM_001292022.2		c.652G>T	p.Gly218Cys	missense	Exon 6 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.1255G>T	p.Gly419Cys	missense	Exon 6 of 11	ENSP00000346206.5
	TAP1	ENST00000698423.1		c.1255G>T	p.Gly419Cys	missense	Exon 6 of 12	ENSP00000513711.1
	TAP1	ENST00000698422.1		c.1255G>T	p.Gly419Cys	missense	Exon 6 of 10	ENSP00000513710.1

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2936 AN: 152096 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0638

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0151

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: 0.000220

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.00487 AC: 943 AN: 193582 AF XY: 0.00365

Gnomad AFR exome AF: 0.0697

Gnomad AMR exome AF: 0.00412

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.00208 AC: 2967 AN: 1428894 Hom.: 87 Cov.: 35 AF XY: 0.00178 AC XY: 1260 AN XY: 707398

African (AFR) AF: 0.0708 AC: 2348 AN: 33184

American (AMR) AF: 0.00528 AC: 203 AN: 38454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25468

East Asian (EAS) AF: 0.00 AC: 0 AN: 38880

South Asian (SAS) AF: 0.000598 AC: 49 AN: 81996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50326

Middle Eastern (MID) AF: 0.00575 AC: 33 AN: 5742

European-Non Finnish (NFE) AF: 0.0000529 AC: 58 AN: 1095470

Other (OTH) AF: 0.00465 AC: 276 AN: 59374

GnomAD4 genome AF: 0.0193 AC: 2942 AN: 152214 Hom.: 89 Cov.: 32 AF XY: 0.0189 AC XY: 1403 AN XY: 74426

African (AFR) AF: 0.0637 AC: 2644 AN: 41502

American (AMR) AF: 0.0150 AC: 230 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68020

Other (OTH) AF: 0.0241 AC: 51 AN: 2112

Alfa AF: 0.00591 Hom.: 111

Bravo AF: 0.0233

ESP6500AA AF: 0.0659 AC: 199

ESP6500EA AF: 0.000554 AC: 3

ExAC AF: 0.00478 AC: 565

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	MHC class I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.0059	T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.41
Sift	Benign	0.030	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.97
MPC		1.6
ClinPred		0.045	T
GERP RS		4.8
Varity_R		0.85
gMVP		0.80
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs2228110; hg19: chr6-32816889;