rs56337036

Positions:

• chr6-32845750-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000593.6(TAP1):​c.2076C>T​(p.Tyr692Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,612,722 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: TAP1 NM_000593.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.398

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:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-32845750-G-A is Benign according to our data. Variant chr6-32845750-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 534729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.398 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00118 (180/152316) while in subpopulation NFE AF= 0.00198 (135/68020). AF 95% confidence interval is 0.00171. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAP1	NM_000593.6	c.2076C>T	p.Tyr692Tyr	synonymous_variant	11/11	ENST00000354258.5	NP_000584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAP1	ENST00000354258.5	c.2076C>T	p.Tyr692Tyr	synonymous_variant	11/11	1	NM_000593.6	ENSP00000346206.5

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00116 AC: 284 AN: 245500 Hom.: 0 AF XY: 0.00130 AC XY: 174 AN XY: 133972

Gnomad AFR exome AF: 0.000332

Gnomad AMR exome AF: 0.000783

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00176 AC: 2569 AN: 1460406 Hom.: 4 Cov.: 31 AF XY: 0.00173 AC XY: 1258 AN XY: 726528

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000115

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74486

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00179 Hom.: 1

Bravo AF: 0.00126

EpiCase AF: 0.00256

EpiControl AF: 0.00326

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class I deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

TAP1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.0
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs56337036; hg19: chr6-32813527;