14-23042569-G-A

Position:

• chr14-23042569-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001099780.2(PSMB11):​c.344G>A​(p.Arg115Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,614,164 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: PSMB11 NM_001099780.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.90

Genes affected

PSMB11 (HGNC:31963): (proteasome subunit beta 11) Proteasomes generate peptides that are presented by major histocompatibility complex (MHC) I molecules to other cells of the immune system. Proteolysis is conducted by 20S proteasomes, complexes of 28 subunits arranged as a cylinder in 4 heteroheptameric rings: alpha-1 to -7, beta-1 to -7, beta-1 to -7, and alpha-1 to -7. The catalytic subunits are beta-1 (PSMB6; MIM 600307), beta-2 (PSMB7; MIM 604030), and beta-5 (PSMB5; MIM 600306). Three additional subunits, beta-1i (PSMB9; MIM 177045), beta-2i (PSMB10; MIM 176847), and beta-5i (PSMB8; MIM 177046), are induced by gamma-interferon (IFNG; MIM 147570) and are preferentially incorporated into proteasomes to make immunoproteasomes. PSMB11, or beta-5t, is a catalytic subunit expressed exclusively in cortical thymic epithelial cells (Murata et al., 2007 [PubMed 17540904]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0143787265).
• BP6: Variant 14-23042569-G-A is Benign according to our data. Variant chr14-23042569-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2644085.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB11	NM_001099780.2	c.344G>A	p.Arg115Gln	missense_variant	1/1	ENST00000408907.5	NP_001093250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB11	ENST00000408907.5	c.344G>A	p.Arg115Gln	missense_variant	1/1		NM_001099780.2	ENSP00000386212	P1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00166 AC: 414 AN: 249208 Hom.: 2 AF XY: 0.00180 AC XY: 244 AN XY: 135216

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00161

Gnomad SAS exome AF: 0.00235

Gnomad FIN exome AF: 0.000604

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00194 AC: 2830 AN: 1461812 Hom.: 5 Cov.: 32 AF XY: 0.00198 AC XY: 1438 AN XY: 727216

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.00282

Gnomad4 FIN exome AF: 0.000712

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.00150 AC XY: 112 AN XY: 74504

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00372

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.00128

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000478 AC: 2

ESP6500EA AF: 0.00154 AC: 13

ExAC AF: 0.00179 AC: 217

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00231

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

PSMB11: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.10
Sift	Benign	0.040	D
Sift4G	Uncertain	0.032	D
Polyphen		0.97	D
Vest4		0.27
MVP		0.58
MPC		0.60
ClinPred		0.022	T
GERP RS		5.2
Varity_R		0.20
gMVP		0.58

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: rs202220440; hg19: chr14-23511778;