rs2228108

Variant names:

• chr6-32853309-G-C
• rs2228108
• NM_000593.6:c.328C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-32853309-G-C
• chr6-32853309-G-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000593.6(TAP1):​c.328C>G​(p.Leu110Val) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,579,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.96
• Publications: 5 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012941211).
• BP6: Variant 6-32853309-G-C is Benign according to our data. Variant chr6-32853309-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 534738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000571 (87/152366) while in subpopulation AFR AF = 0.00192 (80/41598). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	NM_000593.6	MANE Select	c.328C>G	p.Leu110Val	missense	Exon 1 of 11	NP_000584.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	ENST00000354258.5	TSL:1 MANE Select	c.328C>G	p.Leu110Val	missense	Exon 1 of 11	ENSP00000346206.5	Q03518-1
	TAP1	ENST00000698423.1		c.328C>G	p.Leu110Val	missense	Exon 1 of 12	ENSP00000513711.1	A0A8V8TM76
	TAP1	ENST00000920268.1		c.328C>G	p.Leu110Val	missense	Exon 1 of 11	ENSP00000590327.1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000198 AC: 37 AN: 187132 AF XY: 0.000177

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.0000359

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000532 AC: 76 AN: 1427438 Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 34 AN XY: 707194

African (AFR) AF: 0.00210 AC: 69 AN: 32832

American (AMR) AF: 0.0000256 AC: 1 AN: 39050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25514

East Asian (EAS) AF: 0.00 AC: 0 AN: 38140

South Asian (SAS) AF: 0.00 AC: 0 AN: 82916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094276

Other (OTH) AF: 0.000102 AC: 6 AN: 59054

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152366 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74514

African (AFR) AF: 0.00192 AC: 80 AN: 41598

American (AMR) AF: 0.000196 AC: 3 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.000805

ESP6500AA AF: 0.00233 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000207 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.29	N
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.30
Sift	Benign	0.048	D
Sift4G	Benign	0.12	T
Polyphen		0.98	D
Vest4		0.31
MVP		0.90
MPC		1.4
ClinPred		0.051	T
GERP RS		4.0
PromoterAI		0.037	Neutral
Varity_R		0.072
gMVP		0.28
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs2228108; hg19: chr6-32821086;