rs35069201

Positions:

• chr15-43024873-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.2695A>G​(p.Ile899Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,614,138 control chromosomes in the GnomAD database, including 807 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (41 hom., cov: 32)
  • Exomes 𝑓: 0.029 (766 hom.)
• Consequence: UBR1 NM_174916.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.154

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 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=0.0024549663).
• BP6: Variant 15-43024873-T-C is Benign according to our data. Variant chr15-43024873-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 262892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43024873-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0188 (2866/152302) while in subpopulation NFE AF= 0.0304 (2069/68010). AF 95% confidence interval is 0.0293. There are 41 homozygotes in gnomad4. There are 1301 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBR1	NM_174916.3	c.2695A>G	p.Ile899Val	missense_variant	25/47	ENST00000290650.9	NP_777576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBR1	ENST00000290650.9	c.2695A>G	p.Ile899Val	missense_variant	25/47	1	NM_174916.3	ENSP00000290650.4

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2868 AN: 152184 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00647

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0199 AC: 4992 AN: 251424 Hom.: 72 AF XY: 0.0211 AC XY: 2861 AN XY: 135878

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.00778

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0240

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.0292

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0293 AC: 42795 AN: 1461836 Hom.: 766 Cov.: 31 AF XY: 0.0292 AC XY: 21248 AN XY: 727216

Gnomad4 AFR exome AF: 0.00550

Gnomad4 AMR exome AF: 0.00843

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0244

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.0339

Gnomad4 OTH exome AF: 0.0224

GnomAD4 genome AF: 0.0188 AC: 2866 AN: 152302 Hom.: 41 Cov.: 32 AF XY: 0.0175 AC XY: 1301 AN XY: 74486

Gnomad4 AFR AF: 0.00645

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0240

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.0304

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0275 Hom.: 117

Bravo AF: 0.0178

TwinsUK AF: 0.0332 AC: 123

ALSPAC AF: 0.0345 AC: 133

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0302 AC: 260

ExAC AF: 0.0194 AC: 2360

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Johanson-Blizzard syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.41
DANN	Benign	0.41
DEOGEN2	Benign	0.080	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.15	N;.
REVEL	Benign	0.043
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.064
MPC		0.13
ClinPred		0.00095	T
GERP RS		-2.1
Varity_R		0.025
gMVP		0.082

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35069201; hg19: chr15-43317071;