rs2127679

Positions:

• chr6-32850459-G-A
• chr6-32850459-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000593.6(TAP1):​c.1109C>T​(p.Ala370Val) variant causes a missense change. The variant allele was found at a frequency of 0.029 in 1,614,128 control chromosomes in the GnomAD database, including 786 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A370D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (65 hom., cov: 32)
  • Exomes 𝑓: 0.029 (721 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.94

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069664717).
• BP6: Variant 6-32850459-G-A is Benign according to our data. Variant chr6-32850459-G-A is described in ClinVar as [Benign]. Clinvar id is 466377.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32850459-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0281 (4286/152332) while in subpopulation SAS AF= 0.0341 (165/4832). AF 95% confidence interval is 0.0311. There are 65 homozygotes in gnomad4. There are 2112 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 65 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAP1	NM_000593.6	c.1109C>T	p.Ala370Val	missense_variant	5/11	ENST00000354258.5
TAP1	NM_001292022.2	c.506C>T	p.Ala169Val	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAP1	ENST00000354258.5	c.1109C>T	p.Ala370Val	missense_variant	5/11	1	NM_000593.6	P1

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4283 AN: 152214 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0337

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0322

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0276 AC: 6949 AN: 251416 Hom.: 150 AF XY: 0.0284 AC XY: 3854 AN XY: 135892

Gnomad AFR exome AF: 0.0277

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.00962

Gnomad EAS exome AF: 0.000652

Gnomad SAS exome AF: 0.0383

Gnomad FIN exome AF: 0.0356

Gnomad NFE exome AF: 0.0339

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0291 AC: 42481 AN: 1461796 Hom.: 721 Cov.: 31 AF XY: 0.0295 AC XY: 21431 AN XY: 727212

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.0375

Gnomad4 FIN exome AF: 0.0340

Gnomad4 NFE exome AF: 0.0305

Gnomad4 OTH exome AF: 0.0255

GnomAD4 genome AF: 0.0281 AC: 4286 AN: 152332 Hom.: 65 Cov.: 32 AF XY: 0.0284 AC XY: 2112 AN XY: 74492

Gnomad4 AFR AF: 0.0281

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0341

Gnomad4 FIN AF: 0.0360

Gnomad4 NFE AF: 0.0322

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0292 Hom.: 111

Bravo AF: 0.0259

TwinsUK AF: 0.0324 AC: 120

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.0285 AC: 245

ExAC AF: 0.0297 AC: 3608

Asia WGS AF: 0.0280 AC: 99 AN: 3478

EpiCase AF: 0.0302

EpiControl AF: 0.0290

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
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.83	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.070	N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.25
Sift	Benign	0.57	T
Sift4G	Benign	0.28	T
Polyphen		0.0050	B
Vest4		0.018
MPC		0.57
ClinPred		0.0095	T
GERP RS		1.7
Varity_R		0.14
gMVP		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: rs2127679; hg19: chr6-32818236;