11-8224670-C-A

Position:

• chr11-8224670-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002315.3(LMO1):​c.417G>T​(p.Gln139His) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LMO1 NM_002315.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

Genes affected

LMO1 (HGNC:6641): (LIM domain only 1) This locus encodes a transcriptional regulator that contains two cysteine-rich LIM domains but lacks a DNA-binding domain. LIM domains may play a role in protein interactions; thus the encoded protein may regulate transcription by competitively binding to specific DNA-binding transcription factors. Alterations at this locus have been associated with acute lymphoblastic T-cell leukemia. Chromosomal rearrangements have been observed between this locus and at least two loci, the delta subunit of the T-cell antigen receptor gene and the LIM domain binding 1 gene. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2012]

LMO1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMO1	NM_002315.3	c.417G>T	p.Gln139His	missense_variant	4/4	ENST00000335790.8	NP_002306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMO1	ENST00000335790.8	c.417G>T	p.Gln139His	missense_variant	4/4	1	NM_002315.3	ENSP00000338207.3
LMO1	ENST00000428101.6	c.414G>T	p.Gln138His	missense_variant	4/4	1		ENSP00000404538.2
LMO1	ENST00000524379.1	n.564G>T		non_coding_transcript_exon_variant	4/4	1
LMO1	ENST00000534484.1	c.384G>T	p.Gln128His	missense_variant	4/4	5		ENSP00000435456.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459046 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725464

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2024

The c.417G>T (p.Q139H) alteration is located in exon 4 (coding exon 4) of the LMO1 gene. This alteration results from a G to T substitution at nucleotide position 417, causing the glutamine (Q) at amino acid position 139 to be replaced by a histidine (H). 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	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.74
MutPred		0.49		Gain of catalytic residue at Q139 (P = 0.0339);.;.;
MVP		0.99
MPC		1.0
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.70
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-8246217;