Genetic Variant LIME1:p.Arg45Trp (chr20-63737855-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017806.4(LIME1):c.133C>T(p.Arg45Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,561,144 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

LIME1
NM_017806.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0610

Variant links:

Genes affected

LIME1 (HGNC:26016): (Lck interacting transmembrane adaptor 1) This gene encodes a transmembrane adaptor protein that links the T and B-cell receptor stimulation to downstream signaling pathways via its association with the Src family kinases Lck and Lyn, respectively. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Mar 2015]

LIME1 links:

ENSG00000273154 (HGNC:):

ENSG00000273154 links:

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ACMG classification

Classification made for transcript

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=0.07770753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIME1	NM_017806.4 link	c.133C>T	p.Arg45Trp	missense_variant	Exon 3 of 6	ENST00000309546.8	NP_060276.2	Q9H400-1
LIME1	NM_001305654.2 link	c.133C>T	p.Arg45Trp	missense_variant	Exon 3 of 6		NP_001292583.1	Q9H400A0A087WT39
LIME1	NM_001305655.2 link	c.133C>T	p.Arg45Trp	missense_variant	Exon 3 of 6		NP_001292584.1	Q9H400A0A087WT39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIME1	ENST00000309546.8 link	c.133C>T	p.Arg45Trp	missense_variant	Exon 3 of 6	1	NM_017806.4	ENSP00000309521.3		Q9H400-1
ENSG00000273154	ENST00000632538.1 link	c.472C>T	p.Arg158Trp	missense_variant	Exon 4 of 6	3		ENSP00000488802.1		A0A0J9YYD9

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151852

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:

0.000193

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

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

177426

Hom.:

AF XY:

0.0000904

AC XY:

AN XY:

99508

show subpopulations

Gnomad AFR exome

AF:

0.000116

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000682

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000106

AC:

AN:

1409292

Hom.:

Cov.:

AF XY:

0.0000129

AC XY:

AN XY:

699638

show subpopulations

Gnomad4 AFR exome

AF:

0.0000324

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000267

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000274

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74186

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000510

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.133C>T (p.R45W) alteration is located in exon 3 (coding exon 2) of the LIME1 gene. This alteration results from a C to T substitution at nucleotide position 133, causing the arginine (R) at amino acid position 45 to be replaced by a tryptophan (W). 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

0.17

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

.;T;.;.;.;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.74

T;T;T;T;T;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.078

T;T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.7

D;D;.;.;.;.

REVEL

Benign

0.078

Sift

Benign

0.078

T;T;.;.;.;.

Sift4G

Benign

0.080

T;T;T;T;T;D

Polyphen

1.0

.;D;.;.;.;.

Vest4

0.15, 0.21, 0.27

MutPred

0.31

Loss of methylation at R41 (P = 0.039);Loss of methylation at R41 (P = 0.039);Loss of methylation at R41 (P = 0.039);Loss of methylation at R41 (P = 0.039);Loss of methylation at R41 (P = 0.039);.;

MVP

0.62

MPC

0.96

ClinPred

0.40

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.11

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