Genetic Variant UBB:p.Pro189Pro (chr17-16382474-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_018955.4(UBB):c.567C>T(p.Pro189Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0040 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UBB
NM_018955.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.37

Publications

3 publications found

Variant links:

Genes affected

UBB (HGNC:12463): (ubiquitin B) This gene encodes ubiquitin, one of the most conserved proteins known. Ubiquitin has a major role in targeting cellular proteins for degradation by the 26S proteosome. It is also involved in the maintenance of chromatin structure, the regulation of gene expression, and the stress response. Ubiquitin is synthesized as a precursor protein consisting of either polyubiquitin chains or a single ubiquitin moiety fused to an unrelated protein. This gene consists of three direct repeats of the ubiquitin coding sequence with no spacer sequence. Consequently, the protein is expressed as a polyubiquitin precursor with a final amino acid after the last repeat. An aberrant form of this protein has been detected in patients with Alzheimer's disease and Down syndrome. Pseudogenes of this gene are located on chromosomes 1, 2, 13, and 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

UBB Gene-Disease associations (from GenCC):

isolated cleft palate
Inheritance: AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

UBB links:

ENSG00000265401 (HGNC:58390):

ENSG00000265401 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 17-16382474-C-T is Benign according to our data. Variant chr17-16382474-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 728567.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-3.37 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018955.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UBB	NM_018955.4	MANE Select	c.567C>T	p.Pro189Pro	synonymous	Exon 2 of 2	NP_061828.1	P0CG47
UBB	NM_001281716.2		c.567C>T	p.Pro189Pro	synonymous	Exon 2 of 2	NP_001268645.1	Q5U5U6
UBB	NM_001281717.1		c.567C>T	p.Pro189Pro	synonymous	Exon 2 of 2	NP_001268646.1	P0CG47

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UBB	ENST00000302182.8	TSL:1 MANE Select	c.567C>T	p.Pro189Pro	synonymous	Exon 2 of 2	ENSP00000304697.3	P0CG47
UBB	ENST00000395837.1	TSL:2	c.567C>T	p.Pro189Pro	synonymous	Exon 2 of 2	ENSP00000379178.1	P0CG47
UBB	ENST00000395839.5	TSL:2	c.567C>T	p.Pro189Pro	synonymous	Exon 2 of 2	ENSP00000379180.1	P0CG47

Frequencies

GnomAD3 genomes

AF:

0.00395

AC:

456

AN:

115330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00601

Gnomad AMI

AF:

0.00305

Gnomad AMR

AF:

0.00359

Gnomad ASJ

AF:

0.000697

Gnomad EAS

AF:

0.00584

Gnomad SAS

AF:

0.00418

Gnomad FIN

AF:

0.0100

Gnomad MID

AF:

0.0400

Gnomad NFE

AF:

0.00199

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.0000176

AC:

AN:

226688

AF XY:

0.0000243

show subpopulations

Gnomad AFR exome

AF:

0.0000708

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000189

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000153

AC:

AN:

1441212

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

717316

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000154

AC:

AN:

32558

American (AMR)

AF:

0.00

AC:

AN:

41930

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25334

East Asian (EAS)

AF:

0.00

AC:

AN:

38068

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53078

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5514

European-Non Finnish (NFE)

AF:

0.00000908

AC:

AN:

1101118

Other (OTH)

AF:

0.0000850

AC:

AN:

58852

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000678235), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00396

AC:

457

AN:

115398

Hom.:

Cov.:

AF XY:

0.00404

AC XY:

228

AN XY:

56464

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00602

AC:

180

AN:

29888

American (AMR)

AF:

0.00359

AC:

AN:

11422

Ashkenazi Jewish (ASJ)

AF:

0.000697

AC:

AN:

2868

East Asian (EAS)

AF:

0.00586

AC:

AN:

3926

South Asian (SAS)

AF:

0.00448

AC:

AN:

3572

European-Finnish (FIN)

AF:

0.0100

AC:

AN:

7082

Middle Eastern (MID)

AF:

0.0338

AC:

AN:

148

European-Non Finnish (NFE)

AF:

0.00199

AC:

108

AN:

54256

Other (OTH)

AF:

0.00570

AC:

AN:

1580

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.243

Heterozygous variant carriers

149

223

298

372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0109

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.38

(source)

DANN

Benign

0.80

PhyloP100

-3.4

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over