9-126615576-G-C

Variant names:

• chr9-126615576-G-C
• rs1336980
• NM_001174147.2:c.326+7G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001174147.2(LMX1B):​c.326+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,601,354 control chromosomes in the GnomAD database, including 98,592 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7009 hom., cov: 32)
  • Exomes 𝑓: 0.35 (91583 hom.)
• Consequence: LMX1B NM_001174147.2 splice_region, intron
• Scores: Splicing: ADA: 0.2215
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.96
• Publications: 22 publications found

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]

LMX1B Gene-Disease associations (from GenCC):

• nail-patella syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• nail-patella-like renal disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 9-126615576-G-C is Benign according to our data. Variant chr9-126615576-G-C is described in ClinVar as Benign. ClinVar VariationId is 258622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174147.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMX1B	NM_001174147.2	MANE Select	c.326+7G>C		splice_region intron	N/A	NP_001167618.1
	LMX1B	NM_001174146.2		c.326+7G>C		splice_region intron	N/A	NP_001167617.1
	LMX1B	NM_002316.4		c.326+7G>C		splice_region intron	N/A	NP_002307.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMX1B	ENST00000373474.9	TSL:1 MANE Select	c.326+7G>C		splice_region intron	N/A	ENSP00000362573.3
	LMX1B	ENST00000355497.10	TSL:1	c.326+7G>C		splice_region intron	N/A	ENSP00000347684.5
	LMX1B	ENST00000526117.6	TSL:1	c.326+7G>C		splice_region intron	N/A	ENSP00000436930.1

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43070 AN: 151742 Hom.: 7012 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.308

GnomAD2 exomes AF: 0.301 AC: 70307 AN: 233834 AF XY: 0.314

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.363

Gnomad EAS exome AF: 0.0932

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.349 AC: 505613 AN: 1449504 Hom.: 91583 Cov.: 33 AF XY: 0.350 AC XY: 252350 AN XY: 720798

African (AFR) AF: 0.140 AC: 4572 AN: 32728

American (AMR) AF: 0.192 AC: 8416 AN: 43828

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 9385 AN: 25774

East Asian (EAS) AF: 0.121 AC: 4710 AN: 39054

South Asian (SAS) AF: 0.339 AC: 28737 AN: 84744

European-Finnish (FIN) AF: 0.383 AC: 20038 AN: 52312

Middle Eastern (MID) AF: 0.413 AC: 2373 AN: 5740

European-Non Finnish (NFE) AF: 0.368 AC: 406950 AN: 1105572

Other (OTH) AF: 0.342 AC: 20432 AN: 59752

GnomAD4 genome AF: 0.284 AC: 43067 AN: 151850 Hom.: 7009 Cov.: 32 AF XY: 0.285 AC XY: 21112 AN XY: 74192

African (AFR) AF: 0.146 AC: 6034 AN: 41464

American (AMR) AF: 0.260 AC: 3967 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1277 AN: 3468

East Asian (EAS) AF: 0.110 AC: 564 AN: 5106

South Asian (SAS) AF: 0.333 AC: 1602 AN: 4814

European-Finnish (FIN) AF: 0.400 AC: 4218 AN: 10546

Middle Eastern (MID) AF: 0.417 AC: 121 AN: 290

European-Non Finnish (NFE) AF: 0.361 AC: 24535 AN: 67870

Other (OTH) AF: 0.304 AC: 643 AN: 2114

Alfa AF: 0.306 Hom.: 2326

Bravo AF: 0.263

Asia WGS AF: 0.197 AC: 687 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nail-patella syndrome Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nail-patella-like renal disease Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.94
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.22
dbscSNV1_RF	Benign	0.45
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

Other links and lift over

dbSNP: rs1336980; hg19: chr9-129377855; COSMIC: COSV62739324; COSMIC: COSV62739324;