9-126614468-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001174147.2(LMX1B):c.19C>G(p.Pro7Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000437 in 1,578,884 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.73

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06621614).
• BP6: Variant 9-126614468-C-G is Benign according to our data. Variant chr9-126614468-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 364875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMX1B	NM_001174147.2	c.19C>G	p.Pro7Ala	missense_variant	1/8	ENST00000373474.9
LMX1B	NM_001174146.2	c.19C>G	p.Pro7Ala	missense_variant	1/8
LMX1B	NM_002316.4	c.19C>G	p.Pro7Ala	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMX1B	ENST00000373474.9	c.19C>G	p.Pro7Ala	missense_variant	1/8	1	NM_001174147.2	P4
LMX1B	ENST00000355497.10	c.19C>G	p.Pro7Ala	missense_variant	1/8	1
LMX1B	ENST00000526117.6	c.19C>G	p.Pro7Ala	missense_variant	1/8	1		A1

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 151834 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000996 AC: 19 AN: 190812 Hom.: 0 AF XY: 0.0000866 AC XY: 9 AN XY: 103884

Gnomad AFR exome AF: 0.0000923

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000249

Gnomad OTH exome AF: 0.000201

GnomAD4 exome AF: 0.0000406 AC: 58 AN: 1427050 Hom.: 0 Cov.: 31 AF XY: 0.0000354 AC XY: 25 AN XY: 706788

Gnomad4 AFR exome AF: 0.0000612

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000365

Gnomad4 OTH exome AF: 0.0000847

GnomAD4 genome AF: 0.0000724 AC: 11 AN: 151834 Hom.: 0 Cov.: 30 AF XY: 0.0000809 AC XY: 6 AN XY: 74152

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000585 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 23, 2023

- -

Nail-patella syndrome Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Benign	-0.064
Eigen_PC	Benign	-0.0042
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.066	T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.12	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.28	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.37
MVP		0.61
MPC		0.81
ClinPred		0.044	T
GERP RS		2.9
Varity_R		0.13
gMVP		0.47

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs767281663; hg19: chr9-129376747;