rs72924884

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198271.5(LMOD3):c.1270T>C(p.Leu424Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,613,488 control chromosomes in the GnomAD database, including 827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 153 hom., cov: 31)

Exomes 𝑓: 0.026 ( 674 hom. )

Consequence

LMOD3
NM_198271.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.551

Publications

5 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 3-69119085-A-G is Benign according to our data. Variant chr3-69119085-A-G is described in ClinVar as Benign. ClinVar VariationId is 475300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.551 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0607 is higher than 0.05.

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.1270T>C	p.Leu424Leu	synonymous	Exon 2 of 3	NP_938012.2
	LMOD3	NM_001304418.3		c.1270T>C	p.Leu424Leu	synonymous	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.1270T>C	p.Leu424Leu	synonymous	Exon 2 of 3	ENSP00000414670.3
LMOD3	ENST00000475434.1	TSL:5	c.1270T>C	p.Leu424Leu	synonymous	Exon 3 of 4	ENSP00000418645.1
LMOD3	ENST00000489031.5	TSL:2	c.1270T>C	p.Leu424Leu	synonymous	Exon 3 of 4	ENSP00000417210.1

Frequencies

GnomAD3 genomes

AF:

0.0383

AC:

5805

AN:

151674

Hom.:

152

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0581

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0634

Gnomad ASJ

AF:

0.00636

Gnomad EAS

AF:

0.0503

Gnomad SAS

AF:

0.0249

Gnomad FIN

AF:

0.0640

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0189

Gnomad OTH

AF:

0.0407

GnomAD2 exomes

AF:

0.0365

AC:

9088

AN:

249132

AF XY:

0.0334

show subpopulations

Gnomad AFR exome

AF:

0.0630

Gnomad AMR exome

AF:

0.0826

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.0510

Gnomad FIN exome

AF:

0.0627

Gnomad NFE exome

AF:

0.0180

Gnomad OTH exome

AF:

0.0333

GnomAD4 exome

AF:

0.0256

AC:

37426

AN:

1461696

Hom.:

674

Cov.:

AF XY:

0.0250

AC XY:

18202

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0596

AC:

1997

AN:

33480

American (AMR)

AF:

0.0830

AC:

3713

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

268

AN:

26136

East Asian (EAS)

AF:

0.0549

AC:

2178

AN:

39694

South Asian (SAS)

AF:

0.0221

AC:

1903

AN:

86256

European-Finnish (FIN)

AF:

0.0567

AC:

3029

AN:

53402

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0201

AC:

22376

AN:

1111862

Other (OTH)

AF:

0.0312

AC:

1882

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

2367

4734

7101

9468

11835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

962

1924

2886

3848

4810

<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:

0.0383

AC:

5812

AN:

151792

Hom.:

153

Cov.:

AF XY:

0.0400

AC XY:

2965

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.0579

AC:

2397

AN:

41364

American (AMR)

AF:

0.0640

AC:

975

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00636

AC:

AN:

3458

East Asian (EAS)

AF:

0.0500

AC:

259

AN:

5176

South Asian (SAS)

AF:

0.0240

AC:

115

AN:

4784

European-Finnish (FIN)

AF:

0.0640

AC:

674

AN:

10536

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0189

AC:

1281

AN:

67930

Other (OTH)

AF:

0.0402

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

265

530

796

1061

1326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0243

Hom.:

Bravo

AF:

0.0411

Asia WGS

AF:

0.0500

AC:

174

AN:

3478

EpiCase

AF:

0.0186

EpiControl

AF:

0.0181

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Nemaline myopathy 10 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.37

(source)

DANN

Benign

0.60

PhyloP100

0.55

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over