9-126614487-G-A

Variant names:

• chr9-126614487-G-A
• NM_001174147.2:c.38G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001174147.2(LMX1B):​c.38G>A​(p.Cys13Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.54

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.38G>A	p.Cys13Tyr	missense_variant	Exon 1 of 8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.38G>A	p.Cys13Tyr	missense_variant	Exon 1 of 8		NP_001167617.1
LMX1B	NM_002316.4	c.38G>A	p.Cys13Tyr	missense_variant	Exon 1 of 8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.38G>A	p.Cys13Tyr	missense_variant	Exon 1 of 8	1	NM_001174147.2	ENSP00000362573.3
LMX1B	ENST00000355497.10	c.38G>A	p.Cys13Tyr	missense_variant	Exon 1 of 8	1		ENSP00000347684.5
LMX1B	ENST00000526117.6	c.38G>A	p.Cys13Tyr	missense_variant	Exon 1 of 8	1		ENSP00000436930.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449246 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719908

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.38G>A (p.C13Y) alteration is located in exon 1 (coding exon 1) of the LMX1B gene. This alteration results from a G to A substitution at nucleotide position 38, causing the cysteine (C) at amino acid position 13 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0092	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	.;T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Uncertain	-0.012	T
MutationAssessor	Benign	0.34	N;N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.87	N;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.017	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.45
MutPred		0.39		Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);
MVP		0.59
MPC		1.5
ClinPred		0.60	D
GERP RS		3.3
Varity_R		0.43
gMVP		0.51

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-129376766;