Genetic Variant USPL1:p.Ala522Pro (chr13-30657641-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_005800.5(USPL1):c.1564G>C(p.Ala522Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,614,146 control chromosomes in the GnomAD database, including 345 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.018 ( 37 hom., cov: 33)

Exomes 𝑓: 0.018 ( 308 hom. )

Consequence

USPL1
NM_005800.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0800

Publications

10 publications found

Variant links:

Genes affected

USPL1 (HGNC:20294): (ubiquitin specific peptidase like 1) Enables SUMO binding activity and SUMO-specific isopeptidase activity. Involved in several processes, including Cajal body organization; protein desumoylation; and snRNA transcription. Located in Cajal body. [provided by Alliance of Genome Resources, Apr 2022]

USPL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028252602).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0184 (2795/152288) while in subpopulation AMR AF = 0.0238 (364/15298). AF 95% confidence interval is 0.0218. There are 37 homozygotes in GnomAd4. There are 1313 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USPL1	NM_005800.5 link	c.1564G>C	p.Ala522Pro	missense_variant	Exon 9 of 9	ENST00000255304.9	NP_005791.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USPL1	ENST00000255304.9 link	c.1564G>C	p.Ala522Pro	missense_variant	Exon 9 of 9	1	NM_005800.5	ENSP00000255304.4
USPL1	ENST00000614860.1 link	c.577G>C	p.Ala193Pro	missense_variant	Exon 7 of 7	1		ENSP00000480656.1

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2792

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0205

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0238

Gnomad ASJ

AF:

0.0403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00746

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.0478

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.0145

AC:

3647

AN:

251338

AF XY:

0.0145

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.0127

Gnomad ASJ exome

AF:

0.0350

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00268

Gnomad NFE exome

AF:

0.0183

Gnomad OTH exome

AF:

0.0192

GnomAD4 exome

AF:

0.0182

AC:

26546

AN:

1461858

Hom.:

308

Cov.:

AF XY:

0.0179

AC XY:

12990

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0212

AC:

709

AN:

33480

American (AMR)

AF:

0.0134

AC:

600

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0358

AC:

936

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00865

AC:

746

AN:

86256

European-Finnish (FIN)

AF:

0.00232

AC:

124

AN:

53418

Middle Eastern (MID)

AF:

0.0302

AC:

174

AN:

5768

European-Non Finnish (NFE)

AF:

0.0199

AC:

22106

AN:

1111990

Other (OTH)

AF:

0.0190

AC:

1149

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1533

3066

4600

6133

7666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

884

1768

2652

3536

4420

<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:

0.0184

AC:

2795

AN:

152288

Hom.:

Cov.:

AF XY:

0.0176

AC XY:

1313

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0206

AC:

854

AN:

41546

American (AMR)

AF:

0.0238

AC:

364

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0403

AC:

140

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00726

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00330

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0479

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0185

AC:

1259

AN:

68030

Other (OTH)

AF:

0.0255

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

139

279

418

558

697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0175

Hom.:

Bravo

AF:

0.0210

TwinsUK

AF:

0.0224

AC:

ESP6500AA

AF:

0.0229

AC:

101

ESP6500EA

AF:

0.0200

AC:

172

ExAC

AF:

0.0143

AC:

1736

EpiCase

AF:

0.0228

EpiControl

AF:

0.0216

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.4

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0015

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.95

LIST_S2

Benign

0.43

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.2

L;.

PhyloP100

-0.080

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.3

N;.

Sift

Benign

0.40

T;.

Sift4G

Benign

0.27

T;T

Vest4

0.047

ClinPred

0.0065

GERP RS

3.1

Varity_R

0.036

gMVP

0.31

Mutation Taster

=87/13

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over