9-126615576-G-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 258622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-126615576-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.326+7G>C		splice_region_variant, intron_variant	Intron 2 of 7	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.326+7G>C		splice_region_variant, intron_variant	Intron 2 of 7		NP_001167617.1
LMX1B	NM_002316.4	c.326+7G>C		splice_region_variant, intron_variant	Intron 2 of 7		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.326+7G>C		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_001174147.2	ENSP00000362573.3
LMX1B	ENST00000355497.10	c.326+7G>C		splice_region_variant, intron_variant	Intron 2 of 7	1		ENSP00000347684.5
LMX1B	ENST00000526117.6	c.326+7G>C		splice_region_variant, intron_variant	Intron 2 of 7	1		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

GnomAD3 exomes AF: 0.301 AC: 70307 AN: 233834 Hom.: 11739 AF XY: 0.314 AC XY: 39884 AN XY: 127176

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 SAS exome AF: 0.336

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

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.364

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.383

Gnomad4 NFE exome AF: 0.368

Gnomad4 OTH exome AF: 0.342

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

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.260

Gnomad4 ASJ AF: 0.368

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.400

Gnomad4 NFE AF: 0.361

Gnomad4 OTH AF: 0.304

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

-

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.94

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

Publications

LitVar

Other links and lift over

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