chr3-69118700-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_198271.5(LMOD3):c.1655C>A(p.Pro552His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,610,364 control chromosomes in the GnomAD database, including 285 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 23 hom., cov: 30)

Exomes 𝑓: 0.017 ( 262 hom. )

Consequence

LMOD3
NM_198271.5 missense, splice_region

Scores

Splicing: ADA: 0.9584

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 9.47

Publications

9 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 -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 3-69118700-G-T is Benign according to our data. Variant chr3-69118700-G-T is described in ClinVar as Benign. ClinVar VariationId is 475310.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 = 0.013 (1968/151808) while in subpopulation NFE AF = 0.0192 (1304/67942). AF 95% confidence interval is 0.0183. There are 23 homozygotes in GnomAd4. There are 922 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 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.1655C>A	p.Pro552His	missense splice_region	Exon 2 of 3	NP_938012.2
	LMOD3	NM_001304418.3		c.1655C>A	p.Pro552His	missense splice_region	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.1655C>A	p.Pro552His	missense splice_region	Exon 2 of 3	ENSP00000414670.3
LMOD3	ENST00000475434.1	TSL:5	c.1655C>A	p.Pro552His	missense splice_region	Exon 3 of 4	ENSP00000418645.1
LMOD3	ENST00000489031.5	TSL:2	c.1655C>A	p.Pro552His	missense splice_region	Exon 3 of 4	ENSP00000417210.1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1969

AN:

151690

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00439

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0162

Gnomad ASJ

AF:

0.00837

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00105

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0192

Gnomad OTH

AF:

0.0188

GnomAD2 exomes

AF:

0.0124

AC:

3057

AN:

246034

AF XY:

0.0123

show subpopulations

Gnomad AFR exome

AF:

0.00385

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.00801

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.0179

Gnomad OTH exome

AF:

0.0166

GnomAD4 exome

AF:

0.0174

AC:

25410

AN:

1458556

Hom.:

262

Cov.:

AF XY:

0.0169

AC XY:

12247

AN XY:

725406

show subpopulations

African (AFR)

AF:

0.00330

AC:

110

AN:

33320

American (AMR)

AF:

0.0141

AC:

624

AN:

44110

Ashkenazi Jewish (ASJ)

AF:

0.00767

AC:

199

AN:

25946

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39592

South Asian (SAS)

AF:

0.00178

AC:

153

AN:

86002

European-Finnish (FIN)

AF:

0.0157

AC:

837

AN:

53332

Middle Eastern (MID)

AF:

0.0117

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0202

AC:

22455

AN:

1110304

Other (OTH)

AF:

0.0160

AC:

964

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1191

2383

3574

4766

5957

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

836

1672

2508

3344

4180

<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:

0.0130

AC:

1968

AN:

151808

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

922

AN XY:

74154

show subpopulations

African (AFR)

AF:

0.00435

AC:

180

AN:

41376

American (AMR)

AF:

0.0162

AC:

247

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00837

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00105

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.0148

AC:

156

AN:

10548

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0192

AC:

1304

AN:

67942

Other (OTH)

AF:

0.0186

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

188

281

375

469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0169

Hom.:

Bravo

AF:

0.0131

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0195

AC:

ESP6500AA

AF:

0.00461

AC:

ESP6500EA

AF:

0.0169

AC:

140

ExAC

AF:

0.0118

AC:

1423

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29923248)

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LMOD3: BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nemaline myopathy 10

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

European Non-Finnish population allele frequency is 1.729% (rs145387235, 2288/126934 alleles, 23 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0071

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.8

PhyloP100

9.5

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.94

REVEL

Benign

0.18

Sift

Pathogenic

0.0

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.22

MPC

0.17

ClinPred

0.018

GERP RS

5.8

Varity_R

0.37

gMVP

0.18

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.74

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