rs796051859
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_000375.3(UROS):c.397dupG(p.Glu133GlyfsTer65) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
UROS
NM_000375.3 frameshift, splice_region
NM_000375.3 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.448
Publications
0 publications found
Genes affected
UROS (HGNC:12592): (uroporphyrinogen III synthase) The protein encoded by this gene catalyzes the fourth step of porphyrin biosynthesis in the heme biosynthetic pathway. Defects in this gene cause congenital erythropoietic porphyria (Gunther's disease). [provided by RefSeq, Jul 2008]
UROS Gene-Disease associations (from GenCC):
- cutaneous porphyriaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-125798142-T-TC is Pathogenic according to our data. Variant chr10-125798142-T-TC is described in ClinVar as Pathogenic. ClinVar VariationId is 3768.Status of the report is no_assertion_criteria_provided, 0 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000375.3. 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 |
|---|---|---|---|---|---|---|---|---|---|
| UROS | MANE Select | c.397dupG | p.Glu133GlyfsTer65 | frameshift splice_region | Exon 7 of 10 | NP_000366.1 | A0A0S2Z4T8 | ||
| UROS | c.397dupG | p.Glu133GlyfsTer65 | frameshift splice_region | Exon 7 of 11 | NP_001310965.1 | A0A3B3ISM6 | |||
| UROS | c.395-1955dupG | intron | N/A | NP_001310966.1 | A0A3B3ITJ2 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| UROS | TSL:1 MANE Select | c.397dupG | p.Glu133GlyfsTer65 | frameshift splice_region | Exon 7 of 10 | ENSP00000357787.4 | P10746 | ||
| UROS | TSL:1 | c.397dupG | p.Glu133GlyfsTer65 | frameshift splice_region | Exon 6 of 9 | ENSP00000357775.1 | P10746 | ||
| UROS | c.496dupG | p.Glu166GlyfsTer65 | frameshift splice_region | Exon 7 of 11 | ENSP00000610924.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1AN: 1461464Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727014 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1461464
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
727014
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33468
American (AMR)
AF:
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26112
East Asian (EAS)
AF:
AC:
0
AN:
39696
South Asian (SAS)
AF:
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
AC:
0
AN:
53404
Middle Eastern (MID)
AF:
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111672
Other (OTH)
AF:
AC:
0
AN:
60376
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
1
-
-
Cutaneous porphyria (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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