rs57640466

Variant names:

• chr6-32853588-C-G
• rs57640466
• NM_000593.6:c.49G>C
• TAP1 p.Gly17Arg

Your query was ambiguous. Multiple possible variants found:

• chr6-32853588-C-G
• chr6-32853588-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000593.6(TAP1):​c.49G>C​(p.Gly17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,612,552 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (65 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0240
• Publications: 9 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=0.0032283664).
• BP6: Variant 6-32853588-C-G is Benign according to our data. Variant chr6-32853588-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 466385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00823 (1254/152306) while in subpopulation AFR AF = 0.0261 (1087/41572). AF 95% confidence interval is 0.0249. There are 22 homozygotes in GnomAd4. There are 641 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

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.49G>C	p.Gly17Arg	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.49G>C	p.Gly17Arg	missense	Exon 1 of 11	ENSP00000346206.5	Q03518-1
	TAP1	ENST00000698423.1		c.49G>C	p.Gly17Arg	missense	Exon 1 of 12	ENSP00000513711.1	A0A8V8TM76
	TAP1	ENST00000920268.1		c.49G>C	p.Gly17Arg	missense	Exon 1 of 11	ENSP00000590327.1

Frequencies

GnomAD3 genomes AF: 0.00824 AC: 1254 AN: 152188 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00522 AC: 1255 AN: 240344 AF XY: 0.00583

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000224

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000225

Gnomad OTH exome AF: 0.00454

GnomAD4 exome AF: 0.00257 AC: 3754 AN: 1460246 Hom.: 65 Cov.: 32 AF XY: 0.00313 AC XY: 2276 AN XY: 726428

African (AFR) AF: 0.0301 AC: 1009 AN: 33470

American (AMR) AF: 0.00174 AC: 78 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39680

South Asian (SAS) AF: 0.0243 AC: 2093 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52192

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5742

European-Non Finnish (NFE) AF: 0.000325 AC: 361 AN: 1111736

Other (OTH) AF: 0.00321 AC: 194 AN: 60354

GnomAD4 genome AF: 0.00823 AC: 1254 AN: 152306 Hom.: 22 Cov.: 32 AF XY: 0.00861 AC XY: 641 AN XY: 74474

African (AFR) AF: 0.0261 AC: 1087 AN: 41572

American (AMR) AF: 0.00359 AC: 55 AN: 15308

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

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4828

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: 0.000250 AC: 17 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000982 Hom.: 0

Bravo AF: 0.00852

Asia WGS AF: 0.0220 AC: 76 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	MHC class I deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.4
DANN	Benign	0.67
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00035	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.024
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.10
Sift	Benign	0.54	T
Sift4G	Benign	0.89	T
PromoterAI		-0.0079	Neutral
Varity_R		0.15
gMVP		0.15
Mutation Taster		=98/2	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs57640466;

hg19: chr6-32821365;

COSMIC: COSV107445380;

COSMIC: COSV107445380;