9-126614564-C-T

Position:

chr9-126614564-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001174147.2(LMX1B):c.115C>T(p.Pro39Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000376 in 1,595,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

LMX1B
NM_001174147.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.81

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.093158305).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000346 (5/1443448) while in subpopulation EAS AF= 0.000128 (5/38970). AF 95% confidence interval is 0.0000498. There are 0 homozygotes in gnomad4_exome. There are 4 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 GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LMX1B	NM_001174147.2 linkuse as main transcript	c.115C>T	p.Pro39Ser	missense_variant	1/8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2 linkuse as main transcript	c.115C>T	p.Pro39Ser	missense_variant	1/8		NP_001167617.1
LMX1B	NM_002316.4 linkuse as main transcript	c.115C>T	p.Pro39Ser	missense_variant	1/8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9 linkuse as main transcript	c.115C>T	p.Pro39Ser	missense_variant	1/8	1	NM_001174147.2	ENSP00000362573	P4	O60663-1
LMX1B	ENST00000355497.10 linkuse as main transcript	c.115C>T	p.Pro39Ser	missense_variant	1/8	1		ENSP00000347684		O60663-3
LMX1B	ENST00000526117.6 linkuse as main transcript	c.115C>T	p.Pro39Ser	missense_variant	1/8	1		ENSP00000436930	A1	O60663-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152062

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:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000374

AC:

AN:

213984

Hom.:

AF XY:

0.0000339

AC XY:

AN XY:

117946

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000475

Gnomad SAS 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:

0.00000346

AC:

AN:

1443448

Hom.:

Cov.:

AF XY:

0.00000558

AC XY:

AN XY:

717240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000128

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000335

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 22, 2023

The c.115C>T (p.P39S) alteration is located in exon 1 (coding exon 1) of the LMX1B gene. This alteration results from a C to T substitution at nucleotide position 115, causing the proline (P) at amino acid position 39 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Nail-patella syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

May 08, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

.;T;.;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.093

T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.0

N;N;N;.

MutationTaster

Benign

0.64

D;D;D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.24

N;N;N;N

REVEL

Benign

0.21

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;.;.;B

Vest4

0.39

MVP

0.47

MPC

0.74

ClinPred

0.088

GERP RS

3.0

Varity_R

0.046

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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