15-42958014-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_174916.3(UBR1):c.4834A>G(p.Arg1612Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,611,742 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 31 hom. )

Consequence

UBR1
NM_174916.3 missense, splice_region

Scores

Splicing: ADA: 0.5576

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.34

Publications

10 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

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=0.013510913).

BP6

Variant 15-42958014-T-C is Benign according to our data. Variant chr15-42958014-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 437196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00539 (821/152324) while in subpopulation AMR AF = 0.00987 (151/15296). AF 95% confidence interval is 0.00859. There are 5 homozygotes in GnomAd4. There are 394 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174916.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBR1	NM_174916.3	MANE Select	c.4834A>G	p.Arg1612Gly	missense splice_region	Exon 44 of 47	NP_777576.1	Q8IWV7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UBR1	ENST00000290650.9	TSL:1 MANE Select	c.4834A>G	p.Arg1612Gly	missense splice_region	Exon 44 of 47	ENSP00000290650.4	Q8IWV7-1
UBR1	ENST00000914218.1		c.4906A>G	p.Arg1636Gly	missense splice_region	Exon 45 of 48	ENSP00000584277.1
UBR1	ENST00000914217.1		c.4810A>G	p.Arg1604Gly	missense splice_region	Exon 44 of 47	ENSP00000584276.1

Frequencies

GnomAD3 genomes

AF:

0.00539

AC:

820

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00988

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00785

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.00546

AC:

1368

AN:

250758

AF XY:

0.00553

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00581

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00510

Gnomad NFE exome

AF:

0.00804

Gnomad OTH exome

AF:

0.00556

GnomAD4 exome

AF:

0.00610

AC:

8900

AN:

1459418

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

4394

AN XY:

726186

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33450

American (AMR)

AF:

0.00570

AC:

255

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00272

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00183

AC:

158

AN:

86224

European-Finnish (FIN)

AF:

0.00523

AC:

276

AN:

52810

Middle Eastern (MID)

AF:

0.00780

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00699

AC:

7765

AN:

1110316

Other (OTH)

AF:

0.00484

AC:

292

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

401

802

1202

1603

2004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

280

560

840

1120

1400

<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:

0.00539

AC:

821

AN:

152324

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

394

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41580

American (AMR)

AF:

0.00987

AC:

151

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00546

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00785

AC:

534

AN:

68028

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00651

Hom.:

Bravo

AF:

0.00518

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00546

AC:

663

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00823

EpiControl

AF:

0.00895

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

UBR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.42

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.015

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.9

PhyloP100

2.3

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.18

Sift

Benign

0.11

Sift4G

Benign

0.084

Polyphen

0.92

Vest4

0.47

MVP

0.58

MPC

0.38

ClinPred

0.030

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.74

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.56

dbscSNV1_RF

Benign

0.56

SpliceAI score (max)

0.020

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