rs2054389

Variant names:

• chr15-42963923-T-C
• rs2054389
• NM_174916.3:c.4700+12A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-42963923-T-C
• chr15-42963923-T-A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_174916.3(UBR1):​c.4700+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.874 in 1,566,924 control chromosomes in the GnomAD database, including 599,541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (55974 hom., cov: 29)
  • Exomes 𝑓: 0.88 (543567 hom.)
• Consequence: UBR1 NM_174916.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.53
• Publications: 11 publications found

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

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 15-42963923-T-C is Benign according to our data. Variant chr15-42963923-T-C is described in ClinVar as Benign. ClinVar VariationId is 262895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.881 is higher than 0.05.

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.4700+12A>G		intron	N/A	NP_777576.1	Q8IWV7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBR1	ENST00000290650.9	TSL:1 MANE Select	c.4700+12A>G		intron	N/A	ENSP00000290650.4	Q8IWV7-1
	UBR1	ENST00000914218.1		c.4772+12A>G		intron	N/A	ENSP00000584277.1
	UBR1	ENST00000914217.1		c.4676+12A>G		intron	N/A	ENSP00000584276.1

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130231 AN: 151832 Hom.: 55946 Cov.: 29

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.906

Gnomad EAS AF: 0.816

Gnomad SAS AF: 0.886

Gnomad FIN AF: 0.873

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.887

Gnomad OTH AF: 0.870

GnomAD2 exomes AF: 0.864 AC: 216794 AN: 250914 AF XY: 0.869

Gnomad AFR exome AF: 0.803

Gnomad AMR exome AF: 0.832

Gnomad ASJ exome AF: 0.901

Gnomad EAS exome AF: 0.798

Gnomad FIN exome AF: 0.871

Gnomad NFE exome AF: 0.882

Gnomad OTH exome AF: 0.890

GnomAD4 exome AF: 0.876 AC: 1239461 AN: 1414974 Hom.: 543567 Cov.: 23 AF XY: 0.877 AC XY: 620320 AN XY: 707116

African (AFR) AF: 0.792 AC: 25712 AN: 32450

American (AMR) AF: 0.838 AC: 37421 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 23324 AN: 25862

East Asian (EAS) AF: 0.799 AC: 31473 AN: 39388

South Asian (SAS) AF: 0.882 AC: 75243 AN: 85272

European-Finnish (FIN) AF: 0.872 AC: 46429 AN: 53234

Middle Eastern (MID) AF: 0.886 AC: 5041 AN: 5688

European-Non Finnish (NFE) AF: 0.882 AC: 943052 AN: 1069628

Other (OTH) AF: 0.880 AC: 51766 AN: 58822

GnomAD4 genome AF: 0.858 AC: 130311 AN: 151950 Hom.: 55974 Cov.: 29 AF XY: 0.857 AC XY: 63646 AN XY: 74282

African (AFR) AF: 0.802 AC: 33224 AN: 41404

American (AMR) AF: 0.860 AC: 13119 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.906 AC: 3145 AN: 3470

East Asian (EAS) AF: 0.816 AC: 4202 AN: 5148

South Asian (SAS) AF: 0.885 AC: 4262 AN: 4816

European-Finnish (FIN) AF: 0.873 AC: 9217 AN: 10554

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.887 AC: 60328 AN: 67998

Other (OTH) AF: 0.864 AC: 1820 AN: 2106

Alfa AF: 0.872 Hom.: 6615

Bravo AF: 0.852

Asia WGS AF: 0.826 AC: 2871 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Johanson-Blizzard syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	17
DANN	Benign	0.58
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.53		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2054389; hg19: chr15-43256121; COSMIC: COSV51930063;