9-126614564-C-G

Position:

• chr9-126614564-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001174147.2(LMX1B):​c.115C>G​(p.Pro39Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000097 in 1,443,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19572592).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.115C>G	p.Pro39Ala	missense_variant	1/8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.115C>G	p.Pro39Ala	missense_variant	1/8		NP_001167617.1
LMX1B	NM_002316.4	c.115C>G	p.Pro39Ala	missense_variant	1/8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.115C>G	p.Pro39Ala	missense_variant	1/8	1	NM_001174147.2	ENSP00000362573.3
LMX1B	ENST00000355497.10	c.115C>G	p.Pro39Ala	missense_variant	1/8	1		ENSP00000347684.5
LMX1B	ENST00000526117.6	c.115C>G	p.Pro39Ala	missense_variant	1/8	1		ENSP00000436930.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000970 AC: 14 AN: 1443448 Hom.: 0 Cov.: 31 AF XY: 0.00000697 AC XY: 5 AN XY: 717240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000127

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.115C>G (p.P39A) alteration is located in exon 1 (coding exon 1) of the LMX1B gene. This alteration results from a C to G substitution at nucleotide position 115, causing the proline (P) at amino acid position 39 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.29	.;T;.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	-0.90	N;N;N;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.31	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.38	T;T;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.0	.;.;.;B
Vest4		0.32
MVP		0.49
MPC		0.71
ClinPred		0.68	D
GERP RS		3.0
Varity_R		0.045
gMVP		0.41

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

Other links and lift over

dbSNP: rs771784052; hg19: chr9-129376843;