9-126693308-G-C

Position:

• chr9-126693308-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001174147.2(LMX1B):​c.726G>C​(p.Ser242Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,599,944 control chromosomes in the GnomAD database, including 144,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13525 hom., cov: 33)
  • Exomes 𝑓: 0.42 (130665 hom.)
• Consequence: LMX1B NM_001174147.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.205

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 9-126693308-G-C is Benign according to our data. Variant chr9-126693308-G-C is described in ClinVar as [Benign]. Clinvar id is 258629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-126693308-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.205 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.726G>C	p.Ser242Ser	synonymous_variant	4/8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.726G>C	p.Ser242Ser	synonymous_variant	4/8		NP_001167617.1
LMX1B	NM_002316.4	c.726G>C	p.Ser242Ser	synonymous_variant	4/8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.726G>C	p.Ser242Ser	synonymous_variant	4/8	1	NM_001174147.2	ENSP00000362573.3
LMX1B	ENST00000355497.10	c.726G>C	p.Ser242Ser	synonymous_variant	4/8	1		ENSP00000347684.5
LMX1B	ENST00000526117.6	c.726G>C	p.Ser242Ser	synonymous_variant	4/8	1		ENSP00000436930.1

Frequencies

GnomAD3 genomes AF: 0.419 AC: 63677 AN: 151986 Hom.: 13509 Cov.: 33

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.421

GnomAD3 exomes AF: 0.435 AC: 98320 AN: 226044 Hom.: 21268 AF XY: 0.434 AC XY: 53230 AN XY: 122546

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.443

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.554

Gnomad SAS exome AF: 0.435

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.426

Gnomad OTH exome AF: 0.422

GnomAD4 exome AF: 0.423 AC: 612814 AN: 1447840 Hom.: 130665 Cov.: 51 AF XY: 0.424 AC XY: 304814 AN XY: 719362

Gnomad4 AFR exome AF: 0.388

Gnomad4 AMR exome AF: 0.438

Gnomad4 ASJ exome AF: 0.442

Gnomad4 EAS exome AF: 0.524

Gnomad4 SAS exome AF: 0.431

Gnomad4 FIN exome AF: 0.394

Gnomad4 NFE exome AF: 0.420

Gnomad4 OTH exome AF: 0.429

GnomAD4 genome AF: 0.419 AC: 63731 AN: 152104 Hom.: 13525 Cov.: 33 AF XY: 0.418 AC XY: 31082 AN XY: 74362

Gnomad4 AFR AF: 0.395

Gnomad4 AMR AF: 0.426

Gnomad4 ASJ AF: 0.438

Gnomad4 EAS AF: 0.541

Gnomad4 SAS AF: 0.422

Gnomad4 FIN AF: 0.390

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.417

Alfa AF: 0.384 Hom.: 3510

Bravo AF: 0.421

Asia WGS AF: 0.441 AC: 1534 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 55. Only high quality variants are reported. -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Nail-patella syndrome Benign:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 06-18-2018 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Nail-patella-like renal disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.6
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs13295990; hg19: chr9-129455587; COSMIC: COSV62739189;