9-126695900-G-T

Variant names:

• chr9-126695900-G-T
• rs779948246
• NM_001174147.2:c.948G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001174147.2(LMX1B):​c.948G>T​(p.Gln316His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1B	NM_001174147.2	c.948G>T	p.Gln316His	missense_variant	Exon 7 of 8	ENST00000373474.9	NP_001167618.1
LMX1B	NM_001174146.2	c.981G>T	p.Gln327His	missense_variant	Exon 7 of 8		NP_001167617.1
LMX1B	NM_002316.4	c.948G>T	p.Gln316His	missense_variant	Exon 7 of 8		NP_002307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1B	ENST00000373474.9	c.948G>T	p.Gln316His	missense_variant	Exon 7 of 8	1	NM_001174147.2	ENSP00000362573.3
LMX1B	ENST00000355497.10	c.981G>T	p.Gln327His	missense_variant	Exon 7 of 8	1		ENSP00000347684.5
LMX1B	ENST00000526117.6	c.948G>T	p.Gln316His	missense_variant	Exon 7 of 8	1		ENSP00000436930.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000809 AC: 2 AN: 247122 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134220

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: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461246 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726982

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000709 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 316 of the LMX1B protein (p.Gln316His). This variant is present in population databases (rs779948246, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with LMX1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1965374). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LMX1B protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	.;T;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.3	L;L;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.58	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.012	.;.;.;B
Vest4		0.71
MVP		0.63
MPC		0.73
ClinPred		0.15	T
GERP RS		2.6
Varity_R		0.13
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs779948246; hg19: chr9-129458179;