3-69119165-T-C

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.1190A>G(p.Gln397Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00211 in 1,613,880 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q397E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0022 ( 6 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 6.26

Publications

2 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=0.013280481).

BP6

Variant 3-69119165-T-C is Benign according to our data. Variant chr3-69119165-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475293.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00151 (230/152204) while in subpopulation NFE AF = 0.00257 (175/68002). AF 95% confidence interval is 0.00226. There are 1 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	NM_198271.5	MANE Select	c.1190A>G	p.Gln397Arg	missense	Exon 2 of 3	NP_938012.2
	LMOD3	NM_001304418.3		c.1190A>G	p.Gln397Arg	missense	Exon 3 of 4	NP_001291347.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LMOD3	ENST00000420581.7	TSL:1 MANE Select	c.1190A>G	p.Gln397Arg	missense	Exon 2 of 3	ENSP00000414670.3
LMOD3	ENST00000475434.1	TSL:5	c.1190A>G	p.Gln397Arg	missense	Exon 3 of 4	ENSP00000418645.1
LMOD3	ENST00000489031.5	TSL:2	c.1190A>G	p.Gln397Arg	missense	Exon 3 of 4	ENSP00000417210.1

Frequencies

GnomAD3 genomes

AF:

0.00151

AC:

230

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00257

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.00169

AC:

421

AN:

249000

AF XY:

0.00173

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00223

Gnomad NFE exome

AF:

0.00307

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00218

AC:

3180

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

1553

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000358

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00230

AC:

123

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00264

AC:

2934

AN:

1111840

Other (OTH)

AF:

0.00161

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

211

422

633

844

1055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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:

0.00151

AC:

230

AN:

152204

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

119

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000578

AC:

AN:

41522

American (AMR)

AF:

0.00105

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00257

AC:

175

AN:

68002

Other (OTH)

AF:

0.000949

AC:

AN:

2108

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:

0.00202

Hom.:

Bravo

AF:

0.00163

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000776

AC:

ESP6500EA

AF:

0.00265

AC:

ExAC

AF:

0.00187

AC:

226

EpiCase

AF:

0.00213

EpiControl

AF:

0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jul 27, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1190A>G (p.Q397R) alteration is located in exon 2 (coding exon 2) of the LMOD3 gene. This alteration results from a A to G substitution at nucleotide position 1190, causing the glutamine (Q) at amino acid position 397 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Nemaline myopathy 10

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LMOD3-related disorder

Benign:1

Aug 09, 2022

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).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

Eigen

Benign

-0.12

Eigen_PC

Benign

0.049

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.74

M_CAP

Benign

0.056

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.079

MutationAssessor

Benign

1.6

PhyloP100

6.3

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.31

Sift

Benign

0.21

Sift4G

Uncertain

0.059

Polyphen

0.027

Vest4

0.25

MVP

0.88

MPC

0.022

ClinPred

0.043

GERP RS

4.3

Varity_R

0.28

gMVP

0.47

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over