9-126614543-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001174147.2(LMX1B):c.94G>A(p.Glu32Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000345 in 1,451,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.60

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26877564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMX1B	NM_001174147.2	c.94G>A	p.Glu32Lys	missense_variant	1/8	ENST00000373474.9
LMX1B	NM_001174146.2	c.94G>A	p.Glu32Lys	missense_variant	1/8
LMX1B	NM_002316.4	c.94G>A	p.Glu32Lys	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMX1B	ENST00000373474.9	c.94G>A	p.Glu32Lys	missense_variant	1/8	1	NM_001174147.2	P4
LMX1B	ENST00000355497.10	c.94G>A	p.Glu32Lys	missense_variant	1/8	1
LMX1B	ENST00000526117.6	c.94G>A	p.Glu32Lys	missense_variant	1/8	1		A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1451262 Hom.: 0 Cov.: 31 AF XY: 0.00000554 AC XY: 4 AN XY: 721442

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: 0.00000361

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000316 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nail-patella syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.0	N;N;N;.
MutationTaster	Benign	0.86	D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.090	N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.015	D;D;D;D
Sift4G	Benign	0.098	T;T;T;T
Polyphen		0.049	.;.;.;B
Vest4		0.27
MVP		0.40
MPC		1.1
ClinPred		0.75	D
GERP RS		3.0
Varity_R		0.31
gMVP		0.45

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: rs748676035; hg19: chr9-129376822; COSMIC: COSV100827275; COSMIC: COSV100827275;