6-32846670-T-C

Variant names:

• chr6-32846670-T-C
• rs6457684
• NM_000593.6:c.2040+398A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000593.6(TAP1):​c.2040+398A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 151,616 control chromosomes in the GnomAD database, including 12,469 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (12469 hom., cov: 30)
• Consequence: TAP1 NM_000593.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.414
• Publications: 11 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]

PSMB8-AS1 (HGNC:39758): (PSMB8 antisense RNA 1 (head to head))

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAP1	NM_000593.6	c.2040+398A>G		intron_variant	Intron 10 of 10	ENST00000354258.5	NP_000584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAP1	ENST00000354258.5	c.2040+398A>G		intron_variant	Intron 10 of 10	1	NM_000593.6	ENSP00000346206.5

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61011 AN: 151498 Hom.: 12473 Cov.: 30

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.413

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.402 AC: 61007 AN: 151616 Hom.: 12469 Cov.: 30 AF XY: 0.399 AC XY: 29523 AN XY: 74078

African (AFR) AF: 0.364 AC: 15017 AN: 41282

American (AMR) AF: 0.408 AC: 6223 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1287 AN: 3462

East Asian (EAS) AF: 0.423 AC: 2179 AN: 5146

South Asian (SAS) AF: 0.414 AC: 1990 AN: 4808

European-Finnish (FIN) AF: 0.363 AC: 3815 AN: 10496

Middle Eastern (MID) AF: 0.545 AC: 158 AN: 290

European-Non Finnish (NFE) AF: 0.428 AC: 29069 AN: 67886

Other (OTH) AF: 0.408 AC: 859 AN: 2106

Alfa AF: 0.397 Hom.: 1469

Bravo AF: 0.403

Asia WGS AF: 0.392 AC: 1364 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.4
DANN	Benign	0.54
PhyloP100		0.41
Mutation Taster		=100/0	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: rs6457684; hg19: chr6-32814447;