9-126614471-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_001174147.2(LMX1B):c.22G>A(p.Glu8Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000189 in 1,583,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

LMX1B
NM_001174147.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.20

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.4141981).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000196 (28/1431812) while in subpopulation MID AF= 0.000525 (3/5716). AF 95% confidence interval is 0.000142. There are 0 homozygotes in gnomad4_exome. There are 19 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LMX1B	NM_001174147.2 linkuse as main transcript	c.22G>A	p.Glu8Lys	missense_variant	1/8	ENST00000373474.9
LMX1B	NM_001174146.2 linkuse as main transcript	c.22G>A	p.Glu8Lys	missense_variant	1/8
LMX1B	NM_002316.4 linkuse as main transcript	c.22G>A	p.Glu8Lys	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMX1B	ENST00000373474.9 linkuse as main transcript	c.22G>A	p.Glu8Lys	missense_variant	1/8	1	NM_001174147.2	P4	O60663-1
LMX1B	ENST00000355497.10 linkuse as main transcript	c.22G>A	p.Glu8Lys	missense_variant	1/8	1			O60663-3
LMX1B	ENST00000526117.6 linkuse as main transcript	c.22G>A	p.Glu8Lys	missense_variant	1/8	1		A1	O60663-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000253

AC:

AN:

197752

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

107880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000565

Gnomad NFE exome

AF:

0.0000475

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000196

AC:

AN:

1431812

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

709646

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000391

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.0000200

Gnomad4 NFE exome

AF:

0.0000200

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.22G>A (p.E8K) alteration is located in exon 1 (coding exon 1) of the LMX1B gene. This alteration results from a G to A substitution at nucleotide position 22, causing the glutamic acid (E) at amino acid position 8 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 10, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 8 of the LMX1B protein (p.Glu8Lys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1475046). This variant has not been reported in the literature in individuals affected with LMX1B-related conditions. This variant is present in population databases (rs756001518, gnomAD 0.005%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.23

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Benign

-0.010

Eigen_PC

Benign

0.049

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

T;T;T

M_CAP

Pathogenic

0.86

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.34

N;N;N

MutationTaster

Benign

1.0

D;D;N;N;N

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

0.34

N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.090

T;T;T

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.48

MutPred

0.25

Gain of ubiquitination at E8 (P = 0.0121);Gain of ubiquitination at E8 (P = 0.0121);Gain of ubiquitination at E8 (P = 0.0121);

MVP

0.69

MPC

1.0

ClinPred

0.30

GERP RS

2.9

Varity_R

0.25

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over