NM_018640.5:c.422C>T

Variant names:

• chr12-16551238-G-A
• rs1265195965
• NM_018640.5:c.422C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018640.5(LMO3):​c.422C>T​(p.Ala141Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 152,084 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: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMO3 NM_018640.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

Genes affected

LMO3 (HGNC:6643): (LIM domain only 3) The protein encoded by this gene belongs to the rhombotin family of cysteine-rich LIM domain oncogenes. This gene is predominantly expressed in the brain. Related family members, LMO1 and LMO2 on chromosome 11, have been reported to be involved in chromosomal translocations in T-cell leukemia. Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

MGST1 (HGNC:7061): (microsomal glutathione S-transferase 1) The MAPEG (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism) family consists of six human proteins, two of which are involved in the production of leukotrienes and prostaglandin E, important mediators of inflammation. Other family members, demonstrating glutathione S-transferase and peroxidase activities, are involved in cellular defense against toxic, carcinogenic, and pharmacologically active electrophilic compounds. This gene encodes a protein that catalyzes the conjugation of glutathione to electrophiles and the reduction of lipid hydroperoxides. This protein is localized to the endoplasmic reticulum and outer mitochondrial membrane where it is thought to protect these membranes from oxidative stress. Several transcript variants, some non-protein coding and some protein coding, have been found for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18378577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMO3	NM_018640.5	c.422C>T	p.Ala141Val	missense_variant	Exon 4 of 4	ENST00000537304.6	NP_061110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMO3	ENST00000537304.6	c.422C>T	p.Ala141Val	missense_variant	Exon 4 of 4	1	NM_018640.5	ENSP00000440099.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454352 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724040

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

Gnomad4 AFR AF: 0.0000483

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.422C>T (p.A141V) alteration is located in exon 4 (coding exon 3) of the LMO3 gene. This alteration results from a C to T substitution at nucleotide position 422, causing the alanine (A) at amino acid position 141 to be replaced by a valine (V). 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	0.062
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	.;.;.;T;T;T;T;T;T;T;T;.;T
Eigen	Benign	0.032
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;.;.;.;.;.;.;.;D;.
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;.;.;L;L;L;L;L;L;L;L;.;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.12	.;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.72	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.10	.;.;.;B;B;B;B;B;B;B;B;.;B
Vest4		0.22
MutPred		0.30		.;.;.;Loss of methylation at R145 (P = 0.0653);Loss of methylation at R145 (P = 0.0653);Loss of methylation at R145 (P = 0.0653);Loss of methylation at R145 (P = 0.0653);Loss of methylation at R145 (P = 0.0653);Loss of methylation at R145 (P = 0.0653);Loss of methylation at R145 (P = 0.0653);Loss of methylation at R145 (P = 0.0653);.;Loss of methylation at R145 (P = 0.0653);
MVP		0.34
MPC		1.3
ClinPred		0.81	D
GERP RS		3.5
Varity_R		0.17
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1265195965; hg19: chr12-16704172;