rs57640466

Positions:

• chr6-32853588-C-G
• chr6-32853588-C-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.49G>C​(p.Gly17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,612,552 control chromosomes in the GnomAD database, including 87 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0082 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (65 hom.)
• Consequence: TAP1 NM_000593.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0240

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=0.0032283664).
• BP6: Variant 6-32853588-C-G is Benign according to our data. Variant chr6-32853588-C-G is described in ClinVar as [Benign]. Clinvar id is 466385.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32853588-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00823 (1254/152306) while in subpopulation AFR AF= 0.0261 (1087/41572). AF 95% confidence interval is 0.0249. There are 22 homozygotes in gnomad4. There are 641 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAP1	NM_000593.6	c.49G>C	p.Gly17Arg	missense_variant	1/11	ENST00000354258.5	NP_000584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAP1	ENST00000354258.5	c.49G>C	p.Gly17Arg	missense_variant	1/11	1	NM_000593.6	ENSP00000346206	P1

Frequencies

GnomAD3 genomes AF: 0.00824 AC: 1254 AN: 152188 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00522 AC: 1255 AN: 240344 Hom.: 17 AF XY: 0.00583 AC XY: 770 AN XY: 131992

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000224

Gnomad SAS exome AF: 0.0248

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000225

Gnomad OTH exome AF: 0.00454

GnomAD4 exome AF: 0.00257 AC: 3754 AN: 1460246 Hom.: 65 Cov.: 32 AF XY: 0.00313 AC XY: 2276 AN XY: 726428

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000325

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.00823 AC: 1254 AN: 152306 Hom.: 22 Cov.: 32 AF XY: 0.00861 AC XY: 641 AN XY: 74474

Gnomad4 AFR AF: 0.0261

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000982 Hom.: 0

Bravo AF: 0.00852

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0207 AC: 62

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00583 AC: 685

Asia WGS AF: 0.0220 AC: 76 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.4
DANN	Benign	0.67
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00035	N
LIST_S2	Benign	0.54	.;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.20	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.54	N;.
REVEL	Benign	0.10
Sift	Benign	0.54	T;.
Sift4G	Benign	0.89	T;.
Polyphen		0.0010	B;.
Vest4		0.13
MutPred		0.18		Gain of MoRF binding (P = 0.0127);Gain of MoRF binding (P = 0.0127);
MVP		0.51
MPC		0.66
ClinPred		0.000039	T
GERP RS		-0.66
Varity_R		0.15
gMVP		0.15

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: rs57640466; hg19: chr6-32821365;