rs138963231

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_174916.3(UBR1):c.4054-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,607,344 control chromosomes in the GnomAD database, including 260 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 Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 33 hom., cov: 32)

Exomes 𝑓: 0.015 ( 227 hom. )

Consequence

UBR1
NM_174916.3 splice_region, intron

Scores

Splicing: ADA: 0.0001069

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.850

Publications

0 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 15-42983997-G-C is Benign according to our data. Variant chr15-42983997-G-C is described in ClinVar as Benign. ClinVar VariationId is 262893.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 = 0.0124 (1883/152176) while in subpopulation NFE AF = 0.0153 (1039/68008). AF 95% confidence interval is 0.0145. There are 33 homozygotes in GnomAd4. There are 937 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBR1	NM_174916.3 link	c.4054-4C>G		splice_region_variant, intron_variant	Intron 36 of 46	ENST00000290650.9	NP_777576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBR1	ENST00000290650.9 link	c.4054-4C>G		splice_region_variant, intron_variant	Intron 36 of 46	1	NM_174916.3	ENSP00000290650.4		Q8IWV7-1

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1883

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00283

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00642

Gnomad ASJ

AF:

0.0550

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00353

Gnomad FIN

AF:

0.0377

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0153

Gnomad OTH

AF:

0.00863

GnomAD2 exomes

AF:

0.0131

AC:

3269

AN:

249586

AF XY:

0.0130

show subpopulations

Gnomad AFR exome

AF:

0.00278

Gnomad AMR exome

AF:

0.00429

Gnomad ASJ exome

AF:

0.0497

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0338

Gnomad NFE exome

AF:

0.0150

Gnomad OTH exome

AF:

0.0148

GnomAD4 exome

AF:

0.0152

AC:

22188

AN:

1455168

Hom.:

227

Cov.:

AF XY:

0.0150

AC XY:

10860

AN XY:

724258

show subpopulations

African (AFR)

AF:

0.00216

AC:

AN:

33334

American (AMR)

AF:

0.00442

AC:

197

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.0484

AC:

1261

AN:

26058

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39594

South Asian (SAS)

AF:

0.00293

AC:

252

AN:

85892

European-Finnish (FIN)

AF:

0.0365

AC:

1946

AN:

53338

Middle Eastern (MID)

AF:

0.00348

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0159

AC:

17559

AN:

1106452

Other (OTH)

AF:

0.0146

AC:

879

AN:

60186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

923

1845

2768

3690

4613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

684

1368

2052

2736

3420

<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:

0.0124

AC:

1883

AN:

152176

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

937

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00282

AC:

117

AN:

41526

American (AMR)

AF:

0.00641

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0550

AC:

191

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00353

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0377

AC:

399

AN:

10578

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0153

AC:

1039

AN:

68008

Other (OTH)

AF:

0.00854

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

175

262

350

437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0162

Hom.:

Bravo

AF:

0.0103

EpiCase

AF:

0.0152

EpiControl

AF:

0.0148

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Jan 28, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

9.1

(source)

DANN

Benign

0.75

PhyloP100

0.85

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.10

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over