Variant 11-33869374-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005574.4(LMO2):c.220A>C(p.Ile74Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000665 in 150,298 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 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LMO2
NM_005574.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.30

Variant links:

Genes affected

LMO2 (HGNC:6642): (LIM domain only 2) LMO2 encodes a cysteine-rich, two LIM-domain protein that is required for yolk sac erythropoiesis. The LMO2 protein has a central and crucial role in hematopoietic development and is highly conserved. The LMO2 transcription start site is located approximately 25 kb downstream from the 11p13 T-cell translocation cluster (11p13 ttc), where a number T-cell acute lymphoblastic leukemia-specific translocations occur. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Nov 2008]

LMO2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21538588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMO2	NM_005574.4 linkuse as main transcript	c.220A>C	p.Ile74Leu	missense_variant	4/6	ENST00000257818.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMO2	ENST00000257818.3 linkuse as main transcript	c.220A>C	p.Ile74Leu	missense_variant	4/6	1	NM_005574.4		P25791-3
LMO2	ENST00000395833.7 linkuse as main transcript	c.13A>C	p.Ile5Leu	missense_variant	1/3	1		P1	P25791-1
LMO2	ENST00000411482.1 linkuse as main transcript	c.13A>C	p.Ile5Leu	missense_variant, NMD_transcript_variant	1/3	1			P25791-4
LMO2	ENST00000465614.1 linkuse as main transcript	n.787A>C		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150298

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00110

AC:

1019

AN:

930248

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

525

AN XY:

436572

show subpopulations

Gnomad4 AFR exome

AF:

0.00147

Gnomad4 AMR exome

AF:

0.00714

Gnomad4 ASJ exome

AF:

0.00466

Gnomad4 EAS exome

AF:

0.0135

Gnomad4 SAS exome

AF:

0.000389

Gnomad4 FIN exome

AF:

0.00785

Gnomad4 NFE exome

AF:

0.000680

Gnomad4 OTH exome

AF:

0.00200

GnomAD4 genome

AF:

0.00000665

AC:

AN:

150298

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73366

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

The c.220A>C (p.I74L) alteration is located in exon 4 (coding exon 2) of the LMO2 gene. This alteration results from a A to C substitution at nucleotide position 220, causing the isoleucine (I) at amino acid position 74 to be replaced by a leucine (L). 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

0.14

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.33

Cadd

Uncertain

Dann

Benign

0.97

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.82

T;T

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.41

N;N

REVEL

Benign

0.075

Sift

Benign

0.034

D;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0

B;B

Vest4

0.42

MutPred

0.23

Loss of catalytic residue at I5 (P = 0.0189);.;

MVP

0.38

MPC

0.87

ClinPred

0.67

GERP RS

3.3

Varity_R

0.13

gMVP

0.20

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

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