NM_001099780.2:c.145G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_001099780.2(PSMB11):c.145G>A(p.Gly49Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,613,660 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0071 ( 52 hom. )

Consequence

PSMB11
NM_001099780.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 8.96

Publications

14 publications found

Variant links:

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]

PSMB11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.015518874).

BP6

Variant 14-23042370-G-A is Benign according to our data. Variant chr14-23042370-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 771191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00598 (911/152266) while in subpopulation EAS AF = 0.0274 (142/5174). AF 95% confidence interval is 0.0238. There are 7 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB11	NM_001099780.2 link	c.145G>A	p.Gly49Ser	missense_variant	Exon 1 of 1	ENST00000408907.5	NP_001093250.1	A5LHX3B3KVC3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB11	ENST00000408907.5 link	c.145G>A	p.Gly49Ser	missense_variant	Exon 1 of 1	6	NM_001099780.2	ENSP00000386212.2		A5LHX3

Frequencies

GnomAD3 genomes

AF:

0.00595

AC:

906

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.0274

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0114

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00691

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00742

AC:

1848

AN:

248998

AF XY:

0.00743

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00353

Gnomad ASJ exome

AF:

0.00348

Gnomad EAS exome

AF:

0.0220

Gnomad FIN exome

AF:

0.0132

Gnomad NFE exome

AF:

0.00770

Gnomad OTH exome

AF:

0.00810

GnomAD4 exome

AF:

0.00709

AC:

10359

AN:

1461394

Hom.:

Cov.:

AF XY:

0.00710

AC XY:

5162

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33480

American (AMR)

AF:

0.00335

AC:

150

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00371

AC:

AN:

26130

East Asian (EAS)

AF:

0.0256

AC:

1018

AN:

39700

South Asian (SAS)

AF:

0.00220

AC:

190

AN:

86256

European-Finnish (FIN)

AF:

0.0135

AC:

714

AN:

52962

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00692

AC:

7697

AN:

1111992

Other (OTH)

AF:

0.00696

AC:

420

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

657

1315

1972

2630

3287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

298

596

894

1192

1490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00598

AC:

911

AN:

152266

Hom.:

Cov.:

AF XY:

0.00584

AC XY:

435

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41562

American (AMR)

AF:

0.00451

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.0274

AC:

142

AN:

5174

South Asian (SAS)

AF:

0.00207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0114

AC:

121

AN:

10610

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00691

AC:

470

AN:

68004

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00687

Hom.:

Bravo

AF:

0.00549

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000690

AC:

ESP6500EA

AF:

0.00622

AC:

ExAC

AF:

0.00746

AC:

904

EpiCase

AF:

0.00725

EpiControl

AF:

0.00931

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

MetaRNN

Benign

0.016

MetaSVM

Uncertain

0.36

MutationAssessor

Pathogenic

4.0

PhyloP100

9.0

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MVP

0.87

MPC

0.61

ClinPred

0.099

GERP RS

5.4

PromoterAI

0.0021

Neutral

(source)

Varity_R

0.90

gMVP

0.88

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over