9-126614513-G-A

Position:

• chr9-126614513-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001174147.2(LMX1B):​c.64G>A​(p.Ala22Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000027 (0 hom.)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.272

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21807608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMX1B	NM_001174147.2	c.64G>A	p.Ala22Thr	missense_variant	1/8	ENST00000373474.9
LMX1B	NM_001174146.2	c.64G>A	p.Ala22Thr	missense_variant	1/8
LMX1B	NM_002316.4	c.64G>A	p.Ala22Thr	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMX1B	ENST00000373474.9	c.64G>A	p.Ala22Thr	missense_variant	1/8	1	NM_001174147.2	P4
LMX1B	ENST00000355497.10	c.64G>A	p.Ala22Thr	missense_variant	1/8	1
LMX1B	ENST00000526117.6	c.64G>A	p.Ala22Thr	missense_variant	1/8	1		A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455072 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 723462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000680

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.0000166 AC: 2

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

Nov 13, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 22 of the LMX1B protein (p.Ala22Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with LMX1B-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.085
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.16	T;T;T
Vest4		0.081
MutPred		0.28		Gain of phosphorylation at A22 (P = 0.0364);Gain of phosphorylation at A22 (P = 0.0364);Gain of phosphorylation at A22 (P = 0.0364);
MVP		0.64
MPC		0.73
ClinPred		0.12	T
GERP RS		2.0
Varity_R		0.11
gMVP		0.19

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: rs747468994; hg19: chr9-129376792;