rs111797345

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198271.5(LMOD3):c.878G>A(p.Gly293Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,613,904 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 36 hom., cov: 31)

Exomes 𝑓: 0.019 ( 367 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.91

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010550827).

BP6

Variant 3-69119477-C-T is Benign according to our data. Variant chr3-69119477-C-T is described in ClinVar as Benign. ClinVar VariationId is 475334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0151 (2293/152242) while in subpopulation NFE AF = 0.0179 (1218/68008). AF 95% confidence interval is 0.0171. There are 36 homozygotes in GnomAd4. There are 1248 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 36 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMOD3	NM_198271.5 link	c.878G>A	p.Gly293Asp	missense_variant	Exon 2 of 3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3 link	c.878G>A	p.Gly293Asp	missense_variant	Exon 3 of 4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
LMOD3	ENST00000420581.7 link	c.878G>A	p.Gly293Asp	missense_variant	Exon 2 of 3	1	NM_198271.5	ENSP00000414670.3
LMOD3	ENST00000475434.1 link	c.878G>A	p.Gly293Asp	missense_variant	Exon 3 of 4	5		ENSP00000418645.1
LMOD3	ENST00000489031.5 link	c.878G>A	p.Gly293Asp	missense_variant	Exon 3 of 4	2		ENSP00000417210.1

Frequencies

GnomAD3 genomes

AF:

0.0151

AC:

2295

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.0636

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.0169

AC:

4201

AN:

248974

AF XY:

0.0176

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.00863

Gnomad ASJ exome

AF:

0.00925

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0625

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0179

GnomAD4 exome

AF:

0.0189

AC:

27582

AN:

1461662

Hom.:

367

Cov.:

AF XY:

0.0188

AC XY:

13670

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.00242

AC:

AN:

33480

American (AMR)

AF:

0.00892

AC:

399

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00792

AC:

207

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.0151

AC:

1306

AN:

86258

European-Finnish (FIN)

AF:

0.0563

AC:

3005

AN:

53384

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0192

AC:

21354

AN:

1111842

Other (OTH)

AF:

0.0194

AC:

1169

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1685

3370

5056

6741

8426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

816

1632

2448

3264

4080

<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:

0.0151

AC:

2293

AN:

152242

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1248

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00315

AC:

131

AN:

41554

American (AMR)

AF:

0.0103

AC:

157

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0139

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0636

AC:

674

AN:

10598

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0179

AC:

1218

AN:

68008

Other (OTH)

AF:

0.0128

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

111

222

332

443

554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0152

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.0156

AC:

ALSPAC

AF:

0.0223

AC:

ESP6500AA

AF:

0.00323

AC:

ESP6500EA

AF:

0.0189

AC:

158

ExAC

AF:

0.0154

AC:

1867

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0172

EpiControl

AF:

0.0169

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nemaline myopathy 10

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

T;T;T

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.0

.;.;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.2

M;M;M

PhyloP100

7.9

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.62

Sift

Uncertain

0.028

D;D;D

Sift4G

Benign

0.43

T;T;T

Vest4

0.36

ClinPred

0.027

GERP RS

5.7

Varity_R

0.32

gMVP

0.70

Mutation Taster

=95/5

polymorphism (auto)

(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