15-42945444-C-T

Position:

chr15-42945444-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_174916.3(UBR1):c.5135G>A(p.Arg1712His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,884 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1712R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00096 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 7 hom. )

Consequence

UBR1
NM_174916.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -0.415

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), UBR1. . Gene score misZ 2.3964 (greater than the threshold 3.09). Trascript score misZ 3.2935 (greater than threshold 3.09). GenCC has associacion of gene with Johanson-Blizzard syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035677254).

BP6

Variant 15-42945444-C-T is Benign according to our data. Variant chr15-42945444-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 721627.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00096 (146/152016) while in subpopulation EAS AF= 0.00329 (17/5166). AF 95% confidence interval is 0.0021. There are 1 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBR1	NM_174916.3 linkuse as main transcript	c.5135G>A	p.Arg1712His	missense_variant	47/47	ENST00000290650.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBR1	ENST00000290650.9 linkuse as main transcript	c.5135G>A	p.Arg1712His	missense_variant	47/47	1	NM_174916.3	P1	Q8IWV7-1
UBR1	ENST00000562173.1 linkuse as main transcript	n.340G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.000961

AC:

146

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000460

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00328

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000998

AC:

251

AN:

251404

Hom.:

AF XY:

0.000979

AC XY:

133

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00179

Gnomad SAS exome

AF:

0.00140

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00142

AC:

2080

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

1033

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00930

Gnomad4 SAS exome

AF:

0.00146

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00131

Gnomad4 OTH exome

AF:

0.00127

GnomAD4 genome

AF:

0.000960

AC:

146

AN:

152016

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00329

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.0000949

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00119

Hom.:

Bravo

AF:

0.000808

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00111

AC:

135

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	UBR1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 18, 2020	- -

Microcephaly

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

- -

UBR1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2023

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

0.067

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.68

CADD

Benign

3.5

DANN

Benign

0.79

DEOGEN2

Benign

0.091

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.78

M_CAP

Benign

0.0057

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.32

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.13

REVEL

Benign

0.096

Sift

Benign

1.0

Sift4G

Benign

0.16

Polyphen

0.0

Vest4

0.037

MVP

0.18

MPC

0.20

ClinPred

0.0088

GERP RS

-3.9

Varity_R

0.024

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over