6-32853214-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_000593.6(TAP1):c.423T>C(p.Val141=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,611,216 control chromosomes in the GnomAD database, including 955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (90 hom., cov: 32)
  • Exomes 𝑓: 0.031 (865 hom.)
• Consequence: TAP1 NM_000593.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0880

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 6-32853214-A-G is Benign according to our data. Variant chr6-32853214-A-G is described in ClinVar as [Benign]. Clinvar id is 466389.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.088 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP1	NM_000593.6	c.423T>C	p.Val141=	synonymous_variant	1/11	ENST00000354258.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP1	ENST00000354258.5	c.423T>C	p.Val141=	synonymous_variant	1/11	1	NM_000593.6	P1

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4624 AN: 152176 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0518

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0311 AC: 7513 AN: 241300 Hom.: 183 AF XY: 0.0329 AC XY: 4330 AN XY: 131772

Gnomad AFR exome AF: 0.0319

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.00967

Gnomad EAS exome AF: 0.000774

Gnomad SAS exome AF: 0.0624

Gnomad FIN exome AF: 0.0357

Gnomad NFE exome AF: 0.0342

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0313 AC: 45608 AN: 1458922 Hom.: 865 Cov.: 32 AF XY: 0.0324 AC XY: 23474 AN XY: 725576

Gnomad4 AFR exome AF: 0.0339

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.000706

Gnomad4 SAS exome AF: 0.0617

Gnomad4 FIN exome AF: 0.0341

Gnomad4 NFE exome AF: 0.0313

Gnomad4 OTH exome AF: 0.0278

GnomAD4 genome AF: 0.0304 AC: 4626 AN: 152294 Hom.: 90 Cov.: 32 AF XY: 0.0308 AC XY: 2291 AN XY: 74464

Gnomad4 AFR AF: 0.0318

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.0522

Gnomad4 FIN AF: 0.0360

Gnomad4 NFE AF: 0.0331

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0292 Hom.: 88

Bravo AF: 0.0281

Asia WGS AF: 0.0480 AC: 166 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class I deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	4.3
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs55702652; hg19: chr6-32820991;