rs1554728698

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001174147.2(LMX1B):c.736C>T(p.Arg246*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LMX1B
NM_001174147.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.84

Publications

0 publications found

Variant links:

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]

LMX1B Gene-Disease associations (from GenCC):

nail-patella syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P
nail-patella-like renal disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LMX1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 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 9-126693318-C-T is Pathogenic according to our data. Variant chr9-126693318-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 488835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1B	NM_001174147.2 link	c.736C>T	p.Arg246*	stop_gained	Exon 4 of 8	ENST00000373474.9	NP_001167618.1	O60663-1Q6ISE0
LMX1B	NM_001174146.2 link	c.736C>T	p.Arg246*	stop_gained	Exon 4 of 8		NP_001167617.1	B7ZLH2
LMX1B	NM_002316.4 link	c.736C>T	p.Arg246*	stop_gained	Exon 4 of 8		NP_002307.2	O60663-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LMX1B	ENST00000373474.9 link	c.736C>T	p.Arg246*	stop_gained	Exon 4 of 8	1	NM_001174147.2	ENSP00000362573.3	O60663-1
LMX1B	ENST00000355497.10 link	c.736C>T	p.Arg246*	stop_gained	Exon 4 of 8	1		ENSP00000347684.5	O60663-3
LMX1B	ENST00000526117.6 link	c.736C>T	p.Arg246*	stop_gained	Exon 4 of 8	1		ENSP00000436930.1	O60663-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1446374

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718498

African (AFR)

AF:

0.00

AC:

AN:

32976

American (AMR)

AF:

0.00

AC:

AN:

42702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25820

East Asian (EAS)

AF:

0.00

AC:

AN:

38672

South Asian (SAS)

AF:

0.00

AC:

AN:

84130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4564

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105540

Other (OTH)

AF:

0.00

AC:

AN:

59648

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Aug 27, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PP4, PM2, PS4, PVS1 -

Aug 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg246*) 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: 9837817). This variant is also known as R223X. ClinVar contains an entry for this variant (Variation ID: 488835). For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

May 22, 2019

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21184584, 9837817) -

Nail-patella syndrome

Pathogenic:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.87

PhyloP100

1.8

Vest4

0.97

GERP RS

2.9

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over