chr15-43024873-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.2695A>G(p.Ile899Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,614,138 control chromosomes in the GnomAD database, including 807 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 41 hom., cov: 32)

Exomes 𝑓: 0.029 ( 766 hom. )

Consequence

UBR1
NM_174916.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.154

Publications

17 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=0.0024549663).

BP6

Variant 15-43024873-T-C is Benign according to our data. Variant chr15-43024873-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0188 (2866/152302) while in subpopulation NFE AF = 0.0304 (2069/68010). AF 95% confidence interval is 0.0293. There are 41 homozygotes in GnomAd4. There are 1301 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBR1	NM_174916.3 link	c.2695A>G	p.Ile899Val	missense_variant	Exon 25 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.2695A>G	p.Ile899Val	missense_variant	Exon 25 of 47	1	NM_174916.3	ENSP00000290650.4

Frequencies

GnomAD3 genomes

AF:

0.0188

AC:

2868

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00647

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0244

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0304

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.0199

AC:

4992

AN:

251424

AF XY:

0.0211

show subpopulations

Gnomad AFR exome

AF:

0.00671

Gnomad AMR exome

AF:

0.00778

Gnomad ASJ exome

AF:

0.0126

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0143

Gnomad NFE exome

AF:

0.0292

Gnomad OTH exome

AF:

0.0202

GnomAD4 exome

AF:

0.0293

AC:

42795

AN:

1461836

Hom.:

766

Cov.:

AF XY:

0.0292

AC XY:

21248

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00550

AC:

184

AN:

33480

American (AMR)

AF:

0.00843

AC:

377

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

297

AN:

26134

East Asian (EAS)

AF:

0.000176

AC:

AN:

39696

South Asian (SAS)

AF:

0.0244

AC:

2107

AN:

86258

European-Finnish (FIN)

AF:

0.0133

AC:

710

AN:

53420

Middle Eastern (MID)

AF:

0.0166

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0339

AC:

37663

AN:

1111964

Other (OTH)

AF:

0.0224

AC:

1354

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

2370

4741

7111

9482

11852

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1442

2884

4326

5768

7210

<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:

0.0188

AC:

2866

AN:

152302

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1301

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00645

AC:

268

AN:

41572

American (AMR)

AF:

0.0127

AC:

194

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.0240

AC:

116

AN:

4826

European-Finnish (FIN)

AF:

0.0118

AC:

125

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0304

AC:

2069

AN:

68010

Other (OTH)

AF:

0.0161

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

147

294

441

588

735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0270

Hom.:

219

Bravo

AF:

0.0178

TwinsUK

AF:

0.0332

AC:

123

ALSPAC

AF:

0.0345

AC:

133

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0302

AC:

260

ExAC

AF:

0.0194

AC:

2360

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Johanson-Blizzard syndrome

Benign:1

Feb 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.41

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.080

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.63

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;.

PhyloP100

0.15

PrimateAI

Benign

0.25

PROVEAN

Benign

0.15

N;.

REVEL

Benign

0.043

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Vest4

0.064

ClinPred

0.00095

GERP RS

-2.1

Varity_R

0.025

gMVP

0.082

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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