rs2141245282

Variant names:

• chr15-42945359-C-A
• rs2141245282
• NM_174916.3:c.5220G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174916.3(UBR1):​c.5220G>T​(p.Met1740Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UBR1 NM_174916.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08389941).

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.5220G>T	p.Met1740Ile	missense	Exon 47 of 47	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.5220G>T	p.Met1740Ile	missense	Exon 47 of 47	ENSP00000290650.4	Q8IWV7-1
	UBR1	ENST00000914218.1		c.5292G>T	p.Met1764Ile	missense	Exon 48 of 48	ENSP00000584277.1
	UBR1	ENST00000914217.1		c.5196G>T	p.Met1732Ile	missense	Exon 47 of 47	ENSP00000584276.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.0053
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.57	N
PhyloP100		2.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.048
Sift	Benign	0.19	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.45		Loss of disorder (P = 0.1343)
MVP		0.49
MPC		0.18
ClinPred		0.80	D
GERP RS		4.3
Varity_R		0.21
gMVP		0.31
Mutation Taster		=95/5	polymorphism

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: rs2141245282; hg19: chr15-43237557;