9-126696349-C-G

Variant names:

• chr9-126696349-C-G
• NM_001174147.2:c.1107C>G
• LMX1B p.Ser369Arg

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001174147.2(LMX1B):​c.1107C>G​(p.Ser369Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S369S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.195
• Publications: 0 publications found

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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• nail-patella-like renal disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 2.0208 (below the threshold of 3.09). Trascript score misZ: 1.8847 (below the threshold of 3.09). GenCC associations: The gene is linked to nail-patella syndrome, nail-patella-like renal disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174147.2. 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
	LMX1B	NM_001174147.2	MANE Select	c.1107C>G	p.Ser369Arg	missense	Exon 8 of 8	NP_001167618.1	O60663-1
	LMX1B	NM_001174146.2		c.1119C>G	p.Ser373Arg	missense	Exon 8 of 8	NP_001167617.1	O60663-3
	LMX1B	NM_002316.4		c.1086C>G	p.Ser362Arg	missense	Exon 8 of 8	NP_002307.2	O60663-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMX1B	ENST00000373474.9	TSL:1 MANE Select	c.1107C>G	p.Ser369Arg	missense	Exon 8 of 8	ENSP00000362573.3	O60663-1
	LMX1B	ENST00000355497.10	TSL:1	c.1119C>G	p.Ser373Arg	missense	Exon 8 of 8	ENSP00000347684.5	O60663-3
	LMX1B	ENST00000526117.6	TSL:1	c.1086C>G	p.Ser362Arg	missense	Exon 8 of 8	ENSP00000436930.1	O60663-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.20
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.45
Sift	Benign	0.16	T
Sift4G	Benign	0.47	T
Varity_R		0.23
gMVP		0.79
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-129458628;