rs78948790

chr15-42958014-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_174916.3(UBR1):c.4834A>G(p.Arg1612Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,611,742 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (31 hom.)
• Consequence: UBR1 NM_174916.3 missense, splice_region
• Scores: Splicing: ADA: 0.5576
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.34

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, UBR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.013510913).
• BP6: Variant 15-42958014-T-C is Benign according to our data. Variant chr15-42958014-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 437196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42958014-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00539 (821/152324) while in subpopulation AMR AF= 0.00987 (151/15296). AF 95% confidence interval is 0.00859. There are 5 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBR1	NM_174916.3	c.4834A>G	p.Arg1612Gly	missense_variant, splice_region_variant	44/47	ENST00000290650.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBR1	ENST00000290650.9	c.4834A>G	p.Arg1612Gly	missense_variant, splice_region_variant	44/47	1	NM_174916.3	P1

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 820 AN: 152206 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00785

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00546 AC: 1368 AN: 250758 Hom.: 4 AF XY: 0.00553 AC XY: 750 AN XY: 135596

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00581

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00222

Gnomad FIN exome AF: 0.00510

Gnomad NFE exome AF: 0.00804

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00610 AC: 8900 AN: 1459418 Hom.: 31 Cov.: 30 AF XY: 0.00605 AC XY: 4394 AN XY: 726186

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00570

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.00523

Gnomad4 NFE exome AF: 0.00699

Gnomad4 OTH exome AF: 0.00484

GnomAD4 genome AF: 0.00539 AC: 821 AN: 152324 Hom.: 5 Cov.: 32 AF XY: 0.00529 AC XY: 394 AN XY: 74490

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.00785

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00680 Hom.: 4

Bravo AF: 0.00518

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00546 AC: 663

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00823

EpiControl AF: 0.00895

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	UBR1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 07, 2016

- -

UBR1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.18
Sift	Benign	0.11	T
Sift4G	Benign	0.084	T
Polyphen		0.92	P
Vest4		0.47
MVP		0.58
MPC		0.38
ClinPred		0.030	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.56
dbscSNV1_RF	Benign	0.56
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

LitVar

Other links and lift over

dbSNP: rs78948790; hg19: chr15-43250212;