Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2

The ENST00000355497.10(LMX1B):c.904C>T(p.Gln302*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,173,816 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00096 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

LMX1B
ENST00000355497.10 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.237

Publications

0 publications found

Variant links:

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

LMX1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 9-126693830-C-T is Benign according to our data. Variant chr9-126693830-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258630.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00096 (146/152066) while in subpopulation AFR AF = 0.00338 (140/41456). AF 95% confidence interval is 0.00292. There are 1 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 146 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355497.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LMX1B	NM_001174147.2	MANE Select	c.886+18C>T		intron	N/A	NP_001167618.1
LMX1B	NM_001174146.2		c.904C>T	p.Gln302*	stop_gained	Exon 6 of 8	NP_001167617.1
LMX1B	NM_002316.4		c.886+18C>T		intron	N/A	NP_002307.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LMX1B	ENST00000355497.10	TSL:1	c.904C>T	p.Gln302*	stop_gained	Exon 6 of 8	ENSP00000347684.5
LMX1B	ENST00000373474.9	TSL:1 MANE Select	c.886+18C>T		intron	N/A	ENSP00000362573.3
LMX1B	ENST00000526117.6	TSL:1	c.886+18C>T		intron	N/A	ENSP00000436930.1

Frequencies

GnomAD3 genomes

AF:

0.000961

AC:

146

AN:

151948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000108

AC:

AN:

130230

AF XY:

0.0000561

show subpopulations

Gnomad AFR exome

AF:

0.00206

Gnomad AMR exome

AF:

0.0000410

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000910

AC:

AN:

1021750

Hom.:

Cov.:

AF XY:

0.0000675

AC XY:

AN XY:

518390

show subpopulations

African (AFR)

AF:

0.00329

AC:

AN:

24588

American (AMR)

AF:

0.0000569

AC:

AN:

35152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22864

East Asian (EAS)

AF:

0.00

AC:

AN:

34122

South Asian (SAS)

AF:

0.00

AC:

AN:

72056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3568

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

748670

Other (OTH)

AF:

0.000218

AC:

AN:

45960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000960

AC:

146

AN:

152066

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00338

AC:

140

AN:

41456

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000712

Hom.:

Bravo

AF:

0.00111

ExAC

AF:

0.0000588

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

LMX1B-related disorder (1)

Nail-patella syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

6.7

(source)

DANN

Benign

0.96

Eigen

Benign

-0.051

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.0087

PhyloP100

0.24

Vest4

0.23

GERP RS

-0.22

Mutation Taster

=43/157

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs529668402

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over