chr15-42945385-C-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_174916.3(UBR1):c.5194G>T(p.Ala1732Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
UBR1
NM_174916.3 missense
NM_174916.3 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 7.79
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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=0.34435964).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UBR1 | NM_174916.3 | c.5194G>T | p.Ala1732Ser | missense_variant | 47/47 | ENST00000290650.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UBR1 | ENST00000290650.9 | c.5194G>T | p.Ala1732Ser | missense_variant | 47/47 | 1 | NM_174916.3 | P1 | |
UBR1 | ENST00000562173.1 | n.399G>T | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251440Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135904
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461866Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727230
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74324
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 2022 | The c.5194G>T (p.A1732S) alteration is located in exon 47 (coding exon 47) of the UBR1 gene. This alteration results from a G to T substitution at nucleotide position 5194, causing the alanine (A) at amino acid position 1732 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2021 | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1732 of the UBR1 protein (p.Ala1732Ser). This variant is present in population databases (rs760804119, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with UBR1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of disorder (P = 0.0212);
MVP
MPC
ClinPred
D
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at