chr9-126614507-G-A

Position:

• chr9-126614507-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001174147.2(LMX1B):​c.58G>A​(p.Asp20Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,455,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.86

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4040945).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.58G>A	p.Asp20Asn	missense_variant	1/8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.58G>A	p.Asp20Asn	missense_variant	1/8		NP_001167617.1
LMX1B	NM_002316.4	c.58G>A	p.Asp20Asn	missense_variant	1/8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.58G>A	p.Asp20Asn	missense_variant	1/8	1	NM_001174147.2	ENSP00000362573	P4
LMX1B	ENST00000355497.10	c.58G>A	p.Asp20Asn	missense_variant	1/8	1		ENSP00000347684
LMX1B	ENST00000526117.6	c.58G>A	p.Asp20Asn	missense_variant	1/8	1		ENSP00000436930	A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000857 AC: 2 AN: 233506 Hom.: 0 AF XY: 0.00000782 AC XY: 1 AN XY: 127836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1455102 Hom.: 0 Cov.: 31 AF XY: 0.00000691 AC XY: 5 AN XY: 723416

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: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000113

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LMX1B-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2023

The LMX1B c.58G>A variant is predicted to result in the amino acid substitution p.Asp20Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-129376786-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 20 of the LMX1B protein (p.Asp20Asn). This variant is present in population databases (rs758741262, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with LMX1B-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;.
Eigen	Benign	0.048
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.020	N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.026	D;D;D
Sift4G	Benign	0.19	T;T;T
Vest4		0.37
MutPred		0.37		Loss of disorder (P = 0.0729);Loss of disorder (P = 0.0729);Loss of disorder (P = 0.0729);
MVP		0.73
MPC		0.79
ClinPred		0.46	T
GERP RS		3.0
Varity_R		0.16
gMVP		0.34

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: rs758741262; hg19: chr9-129376786;