9-126614485-G-T

Variant summary

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

The NM_001174147.2(LMX1B):c.36G>T(p.Arg12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,924 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: 0.0000021 (0 hom.)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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/exons	MANE	UniProt
LMX1B	NM_001174147.2	c.36G>T	p.Arg12Ser	missense_variant	1/8	ENST00000373474.9
LMX1B	NM_001174146.2	c.36G>T	p.Arg12Ser	missense_variant	1/8
LMX1B	NM_002316.4	c.36G>T	p.Arg12Ser	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMX1B	ENST00000373474.9	c.36G>T	p.Arg12Ser	missense_variant	1/8	1	NM_001174147.2	P4
LMX1B	ENST00000355497.10	c.36G>T	p.Arg12Ser	missense_variant	1/8	1
LMX1B	ENST00000526117.6	c.36G>T	p.Arg12Ser	missense_variant	1/8	1		A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447924 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 719072

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: 0.00000271

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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 13, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with LMX1B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 12 of the LMX1B protein (p.Arg12Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	0.0019	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	-0.027
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.55	N;N;N
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.39	N;N;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.52
MutPred		0.36		Gain of glycosylation at R12 (P = 0.0364);Gain of glycosylation at R12 (P = 0.0364);Gain of glycosylation at R12 (P = 0.0364);
MVP		0.57
MPC		1.8
ClinPred		0.72	D
GERP RS		3.0
Varity_R		0.42
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-129376764;