rs41550019

Variant names:

• chr6-32848995-C-A
• rs41550019
• NM_000593.6:c.1372G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32848995-C-A
• chr6-32848995-C-G
• chr6-32848995-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.1372G>T​(p.Val458Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,612,284 control chromosomes in the GnomAD database, including 1,523 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. V458V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.057 (472 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1051 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.131
• Publications: 12 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=0.0039856136).
• BP6: Variant 6-32848995-C-A is Benign according to our data. Variant chr6-32848995-C-A is described in ClinVar as Benign. ClinVar VariationId is 466381.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	NM_000593.6	MANE Select	c.1372G>T	p.Val458Leu	missense	Exon 6 of 11	NP_000584.3
	TAP1	NM_001292022.2		c.769G>T	p.Val257Leu	missense	Exon 6 of 11	NP_001278951.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAP1	ENST00000354258.5	TSL:1 MANE Select	c.1372G>T	p.Val458Leu	missense	Exon 6 of 11	ENSP00000346206.5
	TAP1	ENST00000698423.1		c.1372G>T	p.Val458Leu	missense	Exon 6 of 12	ENSP00000513711.1
	TAP1	ENST00000920268.1		c.1372G>T	p.Val458Leu	missense	Exon 6 of 11	ENSP00000590327.1

Frequencies

GnomAD3 genomes AF: 0.0566 AC: 8605 AN: 152118 Hom.: 464 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0537

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0602

GnomAD2 exomes AF: 0.0308 AC: 7554 AN: 244888 AF XY: 0.0268

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.0440

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.00122

Gnomad FIN exome AF: 0.00215

Gnomad NFE exome AF: 0.0209

Gnomad OTH exome AF: 0.0407

GnomAD4 exome AF: 0.0256 AC: 37376 AN: 1460048 Hom.: 1051 Cov.: 35 AF XY: 0.0245 AC XY: 17815 AN XY: 726168

African (AFR) AF: 0.139 AC: 4665 AN: 33464

American (AMR) AF: 0.0461 AC: 2049 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3242 AN: 25944

East Asian (EAS) AF: 0.000681 AC: 27 AN: 39668

South Asian (SAS) AF: 0.00430 AC: 369 AN: 85846

European-Finnish (FIN) AF: 0.00227 AC: 121 AN: 53236

Middle Eastern (MID) AF: 0.0585 AC: 334 AN: 5708

European-Non Finnish (NFE) AF: 0.0217 AC: 24085 AN: 1111430

Other (OTH) AF: 0.0412 AC: 2484 AN: 60324

GnomAD4 genome AF: 0.0568 AC: 8644 AN: 152236 Hom.: 472 Cov.: 32 AF XY: 0.0544 AC XY: 4052 AN XY: 74460

African (AFR) AF: 0.137 AC: 5674 AN: 41482

American (AMR) AF: 0.0536 AC: 821 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 451 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4828

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10624

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0223 AC: 1517 AN: 68020

Other (OTH) AF: 0.0595 AC: 126 AN: 2116

Alfa AF: 0.0347 Hom.: 612

Bravo AF: 0.0650

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.124 AC: 376

ESP6500EA AF: 0.0292 AC: 158

ExAC AF: 0.0305 AC: 3696

Asia WGS AF: 0.0170 AC: 61 AN: 3478

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	0.25
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.66	D
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.13
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.33
Sift	Benign	0.24	T
Sift4G	Benign	0.17	T
Polyphen		0.40	B
Vest4		0.12
MutPred		0.34		Gain of sheet (P = 0.0166)
MPC		0.98
ClinPred		0.015	T
GERP RS		4.0
Varity_R		0.095
gMVP		0.66
Mutation Taster		=87/13	polymorphism (auto)

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: rs41550019; hg19: chr6-32816772; COSMIC: COSV99059098; COSMIC: COSV99059098;