rs149196259

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198271.5(LMOD3):c.1519G>A(p.Glu507Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000787 in 1,609,744 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00081 ( 4 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 7.57

Publications

3 publications found

Variant links:

Genes affected

LMOD3 (HGNC:6649): (leiomodin 3) The protein encoded by this gene is a member of the leiomodin family of proteins. This protein contains three actin-binding domains, a tropomyosin domain, a leucine-rich repeat domain, and a Wiskott-Aldrich syndrome protein homology 2 domain (WH2). Localization of this protein to the pointed ends of thin filaments has been observed, and there is evidence that this protein acts as a catalyst of actin nucleation, and is important to the organization of sarcomeric thin filaments in skeletal muscles. Mutations in this gene have been associated as one cause of Nemaline myopathy, as other genes have also been linked to this disorder. Nemaline myopathy is a disorder characterized by nonprogressive generalized muscle weakness and protein inclusions (nemaline bodies) in skeletal myofibers. Patients with mutations in this gene often present with a severe congenital form of the disorder. [provided by RefSeq, Jan 2015]

LMOD3 Gene-Disease associations (from GenCC):

nemaline myopathy 10
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
typical nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe congenital nemaline myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LMOD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06614831).

BP6

Variant 3-69118836-C-T is Benign according to our data. Variant chr3-69118836-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475308.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000533 (79/148156) while in subpopulation NFE AF = 0.00094 (63/67040). AF 95% confidence interval is 0.000753. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMOD3	NM_198271.5 link	c.1519G>A	p.Glu507Lys	missense_variant	Exon 2 of 3	ENST00000420581.7	NP_938012.2	Q0VAK6-1
LMOD3	NM_001304418.3 link	c.1519G>A	p.Glu507Lys	missense_variant	Exon 3 of 4		NP_001291347.1	Q0VAK6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LMOD3	ENST00000420581.7 link	c.1519G>A	p.Glu507Lys	missense_variant	Exon 2 of 3	1	NM_198271.5	ENSP00000414670.3	Q0VAK6-1
LMOD3	ENST00000475434.1 link	c.1519G>A	p.Glu507Lys	missense_variant	Exon 3 of 4	5		ENSP00000418645.1	Q0VAK6-1
LMOD3	ENST00000489031.5 link	c.1519G>A	p.Glu507Lys	missense_variant	Exon 3 of 4	2		ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes

AF:

0.000534

AC:

AN:

148040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000100

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000680

Gnomad ASJ

AF:

0.00292

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000940

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000628

AC:

156

AN:

248604

AF XY:

0.000675

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00289

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000951

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.000813

AC:

1188

AN:

1461588

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

557

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33476

American (AMR)

AF:

0.000380

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00295

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000917

AC:

1020

AN:

1111830

Other (OTH)

AF:

0.00109

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

134

201

268

335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000533

AC:

AN:

148156

Hom.:

Cov.:

AF XY:

0.000556

AC XY:

AN XY:

71974

show subpopulations

African (AFR)

AF:

0.000100

AC:

AN:

40012

American (AMR)

AF:

0.0000679

AC:

AN:

14724

Ashkenazi Jewish (ASJ)

AF:

0.00292

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.000228

AC:

AN:

4384

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000940

AC:

AN:

67040

Other (OTH)

AF:

0.00

AC:

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000843

Hom.:

Bravo

AF:

0.000616

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000251

AC:

ESP6500EA

AF:

0.00156

AC:

ExAC

AF:

0.000703

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1519G>A (p.E507K) alteration is located in exon 2 (coding exon 2) of the LMOD3 gene. This alteration results from a G to A substitution at nucleotide position 1519, causing the glutamic acid (E) at amino acid position 507 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

LMOD3-related disorder

Benign:1

Jul 29, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nemaline myopathy 10

Benign:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Aug 15, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.022

T;T;T

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

.;.;D

M_CAP

Benign

0.060

MetaRNN

Benign

0.066

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;M;M

PhyloP100

7.6

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.22

Sift

Uncertain

0.0020

D;D;D

Sift4G

Benign

0.42

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.64

MVP

0.40

MPC

0.17

ClinPred

0.12

GERP RS

5.8

Varity_R

0.34

gMVP

0.45

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over