Genetic Variant PSME4:p.Ile872Val (chr2-53908799-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_014614.3(PSME4):c.2614A>G(p.Ile872Val) variant causes a missense change. The variant allele was found at a frequency of 0.0325 in 1,602,856 control chromosomes in the GnomAD database, including 3,431 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.050 ( 371 hom., cov: 32)

Exomes 𝑓: 0.031 ( 3060 hom. )

Consequence

PSME4
NM_014614.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.86

Publications

13 publications found

Variant links:

Genes affected

PSME4 (HGNC:20635): (proteasome activator subunit 4) Predicted to enable lysine-acetylated histone binding activity; peptidase activator activity; and proteasome binding activity. Predicted to be involved in DNA repair; proteasomal ubiquitin-independent protein catabolic process; and spermatogenesis, exchange of chromosomal proteins. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PSME4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSME4	NM_014614.3 link	c.2614A>G	p.Ile872Val	missense_variant	Exon 22 of 47	ENST00000404125.6	NP_055429.2	Q14997-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PSME4	ENST00000404125.6 link	c.2614A>G	p.Ile872Val	missense_variant	Exon 22 of 47	1	NM_014614.3	ENSP00000384211.1	Q14997-1
PSME4	ENST00000389993.7 link	n.*747A>G		non_coding_transcript_exon_variant	Exon 21 of 46	1		ENSP00000374643.3	F8WBH5
PSME4	ENST00000389993.7 link	n.*747A>G		3_prime_UTR_variant	Exon 21 of 46	1		ENSP00000374643.3	F8WBH5
PSME4	ENST00000461810.1 link	n.45A>G		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0503

AC:

7648

AN:

151952

Hom.:

369

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0856

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0682

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.219

Gnomad SAS

AF:

0.113

Gnomad FIN

AF:

0.0498

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.0407

GnomAD2 exomes

AF:

0.0615

AC:

15269

AN:

248404

AF XY:

0.0589

show subpopulations

Gnomad AFR exome

AF:

0.0849

Gnomad AMR exome

AF:

0.125

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.201

Gnomad FIN exome

AF:

0.0443

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.0465

GnomAD4 exome

AF:

0.0306

AC:

44460

AN:

1450786

Hom.:

3060

Cov.:

AF XY:

0.0324

AC XY:

23395

AN XY:

722372

show subpopulations

African (AFR)

AF:

0.0820

AC:

2697

AN:

32910

American (AMR)

AF:

0.117

AC:

5132

AN:

43760

Ashkenazi Jewish (ASJ)

AF:

0.0132

AC:

342

AN:

25876

East Asian (EAS)

AF:

0.280

AC:

11039

AN:

39424

South Asian (SAS)

AF:

0.113

AC:

9682

AN:

85466

European-Finnish (FIN)

AF:

0.0432

AC:

2303

AN:

53322

Middle Eastern (MID)

AF:

0.0375

AC:

214

AN:

5702

European-Non Finnish (NFE)

AF:

0.00978

AC:

10797

AN:

1104460

Other (OTH)

AF:

0.0377

AC:

2254

AN:

59866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1715

3430

5146

6861

8576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

698

1396

2094

2792

3490

<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:

0.0504

AC:

7661

AN:

152070

Hom.:

371

Cov.:

AF XY:

0.0544

AC XY:

4041

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0855

AC:

3551

AN:

41516

American (AMR)

AF:

0.0687

AC:

1049

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3466

East Asian (EAS)

AF:

0.219

AC:

1133

AN:

5164

South Asian (SAS)

AF:

0.113

AC:

543

AN:

4810

European-Finnish (FIN)

AF:

0.0498

AC:

527

AN:

10592

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0106

AC:

720

AN:

67942

Other (OTH)

AF:

0.0413

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

347

693

1040

1386

1733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<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:

0.0276

Hom.:

935

Bravo

AF:

0.0530

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.0888

AC:

391

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.0612

AC:

7423

Asia WGS

AF:

0.139

AC:

483

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.067

Eigen

Benign

-0.11

Eigen_PC

Benign

0.096

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

3.9

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.19

REVEL

Benign

0.13

Sift

Benign

0.077

Sift4G

Benign

0.85

Polyphen

0.0010

Vest4

0.031

MPC

0.22

ClinPred

0.019

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.090

gMVP

0.22

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: 1

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

Computational scores

Splicing

Publications

Other links and lift over