rs121909487
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_001174147.2(LMX1B):c.661C>T(p.Arg221Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
LMX1B
NM_001174147.2 stop_gained
NM_001174147.2 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.92
Genes affected
LMX1B (HGNC:6654): (LIM homeobox transcription factor 1 beta) This gene encodes a member of LIM-homeodomain family of proteins containing two N-terminal zinc-binding LIM domains, 1 homeodomain, and a C-terminal glutamine-rich domain. It functions as a transcription factor, and is essential for the normal development of dorsal limb structures, the glomerular basement membrane, the anterior segment of the eye, and dopaminergic and serotonergic neurons. Mutations in this gene are associated with nail-patella syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 9-126693243-C-T is Pathogenic according to our data. Variant chr9-126693243-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7001.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-126693243-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMX1B | NM_001174147.2 | c.661C>T | p.Arg221Ter | stop_gained | 4/8 | ENST00000373474.9 | |
LMX1B | NM_001174146.2 | c.661C>T | p.Arg221Ter | stop_gained | 4/8 | ||
LMX1B | NM_002316.4 | c.661C>T | p.Arg221Ter | stop_gained | 4/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMX1B | ENST00000373474.9 | c.661C>T | p.Arg221Ter | stop_gained | 4/8 | 1 | NM_001174147.2 | P4 | |
LMX1B | ENST00000355497.10 | c.661C>T | p.Arg221Ter | stop_gained | 4/8 | 1 | |||
LMX1B | ENST00000526117.6 | c.661C>T | p.Arg221Ter | stop_gained | 4/8 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1459108Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 725670
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1459108
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
725670
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change creates a premature translational stop signal (p.Arg221*) in the LMX1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMX1B are known to be pathogenic (PMID: 9590287, 15498463). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with nail-patella syndrome (PMID: 9590287, 24720768). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7001). For these reasons, this variant has been classified as Pathogenic. - |
Nail-patella syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1998 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A
Vest4
GERP RS
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