9-126693527-C-G

Variant names:

• chr9-126693527-C-G
• rs121909492
• NM_001174147.2:c.745C>G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001174147.2(LMX1B):​c.745C>G​(p.Arg249Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R249P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.74

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity LMX1B_HUMAN there are 43 pathogenic changes around while only 0 benign (100%) in NM_001174147.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-126693528-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 9-126693527-C-G is Pathogenic according to our data. Variant chr9-126693527-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 666319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-126693527-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.745C>G	p.Arg249Gly	missense_variant	Exon 5 of 8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.745C>G	p.Arg249Gly	missense_variant	Exon 5 of 8		NP_001167617.1
LMX1B	NM_002316.4	c.745C>G	p.Arg249Gly	missense_variant	Exon 5 of 8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.745C>G	p.Arg249Gly	missense_variant	Exon 5 of 8	1	NM_001174147.2	ENSP00000362573.3
LMX1B	ENST00000355497.10	c.745C>G	p.Arg249Gly	missense_variant	Exon 5 of 8	1		ENSP00000347684.5
LMX1B	ENST00000526117.6	c.745C>G	p.Arg249Gly	missense_variant	Exon 5 of 8	1		ENSP00000436930.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nail-patella syndrome;C0403548:Nail-patella-like renal disease Pathogenic:1

Feb 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nail-patella syndrome Pathogenic:1

Jan 01, 2014

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;D
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.6	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.92
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.93
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs121909492; hg19: chr9-129455806;