rs10733682

Positions:

• chr9-126698635-A-G
• chr9-126698635-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001174147.2(LMX1B):​c.*2184A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 152,168 control chromosomes in the GnomAD database, including 23,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23756 hom., cov: 32)
  • Exomes 𝑓: 0.48 (19 hom.)
• Consequence: LMX1B NM_001174147.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.321

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 9-126698635-A-G is Benign according to our data. Variant chr9-126698635-A-G is described in ClinVar as [Benign]. Clinvar id is 364952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.*2184A>G		3_prime_UTR_variant	8/8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.*2184A>G		3_prime_UTR_variant	8/8		NP_001167617.1
LMX1B	NM_002316.4	c.*2184A>G		3_prime_UTR_variant	8/8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.*2184A>G		3_prime_UTR_variant	8/8	1	NM_001174147.2	ENSP00000362573	P4
LMX1B	ENST00000355497.10	c.*2184A>G		3_prime_UTR_variant	8/8	1		ENSP00000347684
LMX1B	ENST00000526117.6	c.*2184A>G		3_prime_UTR_variant	8/8	1		ENSP00000436930	A1

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82837 AN: 151868 Hom.: 23704 Cov.: 32

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.533

GnomAD4 exome AF: 0.478 AC: 87 AN: 182 Hom.: 19 Cov.: 0 AF XY: 0.492 AC XY: 62 AN XY: 126

Gnomad4 AFR exome AF: 0.750

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.450

Gnomad4 NFE exome AF: 0.484

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.546 AC: 82949 AN: 151986 Hom.: 23756 Cov.: 32 AF XY: 0.538 AC XY: 39954 AN XY: 74286

Gnomad4 AFR AF: 0.718

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.520

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.436

Gnomad4 FIN AF: 0.461

Gnomad4 NFE AF: 0.516

Gnomad4 OTH AF: 0.536

Alfa AF: 0.512 Hom.: 29105

Bravo AF: 0.548

Asia WGS AF: 0.413 AC: 1439 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Nail-patella syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Benign	0.91

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10733682; hg19: chr9-129460914;