15-42963993-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_174916.3(UBR1):c.4642A>G(p.Thr1548Ala) variant causes a missense change. The variant allele was found at a frequency of 0.07 in 1,612,558 control chromosomes in the GnomAD database, including 4,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 315 hom., cov: 32)

Exomes 𝑓: 0.072 ( 4260 hom. )

Consequence

UBR1
NM_174916.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.99

Publications

18 publications found

Variant links:

Genes affected

UBR1 (HGNC:16808): (ubiquitin protein ligase E3 component n-recognin 1) The N-end rule pathway is one proteolytic pathway of the ubiquitin system. The recognition component of this pathway, encoded by this gene, binds to a destabilizing N-terminal residue of a substrate protein and participates in the formation of a substrate-linked multiubiquitin chain. This leads to the eventual degradation of the substrate protein. The protein described in this record has a RING-type zinc finger and a UBR-type zinc finger. Mutations in this gene have been associated with Johanson-Blizzard syndrome. [provided by RefSeq, Jul 2008]

UBR1 Gene-Disease associations (from GenCC):

Johanson-Blizzard syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

UBR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034118295).

BP6

Variant 15-42963993-T-C is Benign according to our data. Variant chr15-42963993-T-C is described in ClinVar as [Benign]. Clinvar id is 262894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBR1	NM_174916.3 link	c.4642A>G	p.Thr1548Ala	missense_variant	Exon 42 of 47	ENST00000290650.9	NP_777576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBR1	ENST00000290650.9 link	c.4642A>G	p.Thr1548Ala	missense_variant	Exon 42 of 47	1	NM_174916.3	ENSP00000290650.4		Q8IWV7-1

Frequencies

GnomAD3 genomes

AF:

0.0532

AC:

8083

AN:

152070

Hom.:

315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.0332

Gnomad ASJ

AF:

0.0795

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0949

Gnomad FIN

AF:

0.0773

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0772

Gnomad OTH

AF:

0.0594

GnomAD2 exomes

AF:

0.0629

AC:

15797

AN:

251252

AF XY:

0.0679

show subpopulations

Gnomad AFR exome

AF:

0.0120

Gnomad AMR exome

AF:

0.0296

Gnomad ASJ exome

AF:

0.0803

Gnomad EAS exome

AF:

0.000652

Gnomad FIN exome

AF:

0.0752

Gnomad NFE exome

AF:

0.0747

Gnomad OTH exome

AF:

0.0728

GnomAD4 exome

AF:

0.0717

AC:

104754

AN:

1460370

Hom.:

4260

Cov.:

AF XY:

0.0736

AC XY:

53492

AN XY:

726586

show subpopulations

African (AFR)

AF:

0.0108

AC:

362

AN:

33464

American (AMR)

AF:

0.0308

AC:

1377

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0820

AC:

2141

AN:

26110

East Asian (EAS)

AF:

0.000353

AC:

AN:

39664

South Asian (SAS)

AF:

0.107

AC:

9239

AN:

86218

European-Finnish (FIN)

AF:

0.0731

AC:

3899

AN:

53358

Middle Eastern (MID)

AF:

0.105

AC:

603

AN:

5762

European-Non Finnish (NFE)

AF:

0.0748

AC:

83035

AN:

1110752

Other (OTH)

AF:

0.0677

AC:

4084

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

4519

9037

13556

18074

22593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3014

6028

9042

12056

15070

<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:

0.0531

AC:

8082

AN:

152188

Hom.:

315

Cov.:

AF XY:

0.0543

AC XY:

4038

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0132

AC:

547

AN:

41546

American (AMR)

AF:

0.0331

AC:

506

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0795

AC:

276

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.0947

AC:

457

AN:

4824

European-Finnish (FIN)

AF:

0.0773

AC:

819

AN:

10594

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0772

AC:

5247

AN:

67982

Other (OTH)

AF:

0.0592

AC:

125

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

375

750

1125

1500

1875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0670

Hom.:

1096

Bravo

AF:

0.0467

TwinsUK

AF:

0.0758

AC:

281

ALSPAC

AF:

0.0758

AC:

292

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.0735

AC:

632

ExAC

AF:

0.0635

AC:

7714

Asia WGS

AF:

0.0290

AC:

102

AN:

3478

EpiCase

AF:

0.0761

EpiControl

AF:

0.0768

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

0.11

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0034

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.97

PhyloP100

5.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.5

REVEL

Benign

0.090

Sift

Benign

0.20

Sift4G

Uncertain

0.034

Polyphen

0.70

Vest4

0.19

MPC

0.35

ClinPred

0.0086

GERP RS

4.7

Varity_R

0.11

gMVP

0.23

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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