9-126614469-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001174147.2(LMX1B):c.20C>G(p.Pro7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,580,674 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1753898).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000049 (7/1428838) while in subpopulation EAS AF= 0.000185 (7/37880). AF 95% confidence interval is 0.0000865. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMX1B	NM_001174147.2	c.20C>G	p.Pro7Arg	missense_variant	1/8	ENST00000373474.9
LMX1B	NM_001174146.2	c.20C>G	p.Pro7Arg	missense_variant	1/8
LMX1B	NM_002316.4	c.20C>G	p.Pro7Arg	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMX1B	ENST00000373474.9	c.20C>G	p.Pro7Arg	missense_variant	1/8	1	NM_001174147.2	P4
LMX1B	ENST00000355497.10	c.20C>G	p.Pro7Arg	missense_variant	1/8	1
LMX1B	ENST00000526117.6	c.20C>G	p.Pro7Arg	missense_variant	1/8	1		A1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151836 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000310 AC: 6 AN: 193488 Hom.: 0 AF XY: 0.0000190 AC XY: 2 AN XY: 105312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000406

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000490 AC: 7 AN: 1428838 Hom.: 0 Cov.: 31 AF XY: 0.00000424 AC XY: 3 AN XY: 707814

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000185

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151836 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74144

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000251 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2023

The c.20C>G (p.P7R) alteration is located in exon 1 (coding exon 1) of the LMX1B gene. This alteration results from a C to G substitution at nucleotide position 20, causing the proline (P) at amino acid position 7 to be replaced by an arginine (R). 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	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.056
Eigen_PC	Benign	-0.00089
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.76	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.079	T;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.55
MutPred		0.30		Gain of solvent accessibility (P = 0.0411);Gain of solvent accessibility (P = 0.0411);Gain of solvent accessibility (P = 0.0411);
MVP		0.55
MPC		1.4
ClinPred		0.16	T
GERP RS		2.9
Varity_R		0.21
gMVP		0.58

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: rs750263789; hg19: chr9-129376748;