rs4924704

Variant names:

• chr15-43059843-G-A
• rs4924704
• NM_174916.3:c.862-18C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-43059843-G-A
• chr15-43059843-G-C
• chr15-43059843-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174916.3(UBR1):​c.862-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 1,613,096 control chromosomes in the GnomAD database, including 615,229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (55913 hom., cov: 30)
  • Exomes 𝑓: 0.87 (559316 hom.)
• Consequence: UBR1 NM_174916.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.983
• Publications: 15 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-43059843-G-A is Benign according to our data. Variant chr15-43059843-G-A is described in ClinVar as Benign. ClinVar VariationId is 262898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.88 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBR1	NM_174916.3	MANE Select	c.862-18C>T		intron	N/A	NP_777576.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBR1	ENST00000290650.9	TSL:1 MANE Select	c.862-18C>T		intron	N/A	ENSP00000290650.4
	UBR1	ENST00000546274.6	TSL:2	c.862-18C>T		intron	N/A	ENSP00000477932.1
	UBR1	ENST00000563239.1	TSL:3	n.*202+11056C>T		intron	N/A	ENSP00000456502.1

Frequencies

GnomAD3 genomes AF: 0.857 AC: 130236 AN: 152022 Hom.: 55885 Cov.: 30

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.819

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.905

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.885

Gnomad FIN AF: 0.871

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.886

Gnomad OTH AF: 0.868

GnomAD2 exomes AF: 0.863 AC: 216337 AN: 250780 AF XY: 0.867

Gnomad AFR exome AF: 0.802

Gnomad AMR exome AF: 0.831

Gnomad ASJ exome AF: 0.897

Gnomad EAS exome AF: 0.797

Gnomad FIN exome AF: 0.869

Gnomad NFE exome AF: 0.881

Gnomad OTH exome AF: 0.888

GnomAD4 exome AF: 0.874 AC: 1277593 AN: 1460956 Hom.: 559316 Cov.: 45 AF XY: 0.876 AC XY: 636478 AN XY: 726826

African (AFR) AF: 0.791 AC: 26449 AN: 33450

American (AMR) AF: 0.837 AC: 37418 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.899 AC: 23491 AN: 26126

East Asian (EAS) AF: 0.795 AC: 31543 AN: 39676

South Asian (SAS) AF: 0.882 AC: 76020 AN: 86234

European-Finnish (FIN) AF: 0.870 AC: 46480 AN: 53400

Middle Eastern (MID) AF: 0.885 AC: 5102 AN: 5764

European-Non Finnish (NFE) AF: 0.880 AC: 978078 AN: 1111240

Other (OTH) AF: 0.878 AC: 53012 AN: 60362

GnomAD4 genome AF: 0.857 AC: 130315 AN: 152140 Hom.: 55913 Cov.: 30 AF XY: 0.856 AC XY: 63654 AN XY: 74388

African (AFR) AF: 0.802 AC: 33264 AN: 41472

American (AMR) AF: 0.859 AC: 13117 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.905 AC: 3141 AN: 3472

East Asian (EAS) AF: 0.812 AC: 4199 AN: 5170

South Asian (SAS) AF: 0.884 AC: 4265 AN: 4824

European-Finnish (FIN) AF: 0.871 AC: 9229 AN: 10590

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

European-Non Finnish (NFE) AF: 0.886 AC: 60284 AN: 68020

Other (OTH) AF: 0.862 AC: 1818 AN: 2110

Alfa AF: 0.873 Hom.: 12154

Bravo AF: 0.851

Asia WGS AF: 0.826 AC: 2871 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Johanson-Blizzard syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.1
DANN	Benign	0.34
PhyloP100		0.98
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4924704; hg19: chr15-43352041; COSMIC: COSV51930102; COSMIC: COSV51930102;