chr3-69122139-C-T

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.248G>A(p.Arg83His) variant causes a missense change. The variant allele was found at a frequency of 0.0323 in 1,612,120 control chromosomes in the GnomAD database, including 980 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R83C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.025 ( 58 hom., cov: 32)

Exomes 𝑓: 0.033 ( 922 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.06

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004994124).

BP6

Variant 3-69122139-C-T is Benign according to our data. Variant chr3-69122139-C-T is described in ClinVar as Benign. ClinVar VariationId is 475315.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 = 0.0248 (3777/152208) while in subpopulation NFE AF = 0.0386 (2628/68024). AF 95% confidence interval is 0.0374. There are 58 homozygotes in GnomAd4. There are 1756 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 58 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMOD3	NM_198271.5 link	c.248G>A	p.Arg83His	missense_variant	Exon 1 of 3	ENST00000420581.7	NP_938012.2	Q0VAK6-1
LMOD3	NM_001304418.3 link	c.248G>A	p.Arg83His	missense_variant	Exon 2 of 4		NP_001291347.1	Q0VAK6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LMOD3	ENST00000420581.7 link	c.248G>A	p.Arg83His	missense_variant	Exon 1 of 3	1	NM_198271.5	ENSP00000414670.3	Q0VAK6-1
LMOD3	ENST00000475434.1 link	c.248G>A	p.Arg83His	missense_variant	Exon 2 of 4	5		ENSP00000418645.1	Q0VAK6-1
LMOD3	ENST00000489031.5 link	c.248G>A	p.Arg83His	missense_variant	Exon 2 of 4	2		ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes

AF:

0.0248

AC:

3778

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00813

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0216

Gnomad ASJ

AF:

0.0352

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00892

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0386

Gnomad OTH

AF:

0.0279

GnomAD2 exomes

AF:

0.0253

AC:

6218

AN:

246150

AF XY:

0.0252

show subpopulations

Gnomad AFR exome

AF:

0.00643

Gnomad AMR exome

AF:

0.0114

Gnomad ASJ exome

AF:

0.0355

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0253

Gnomad NFE exome

AF:

0.0390

Gnomad OTH exome

AF:

0.0253

GnomAD4 exome

AF:

0.0330

AC:

48225

AN:

1459912

Hom.:

922

Cov.:

AF XY:

0.0323

AC XY:

23479

AN XY:

726026

show subpopulations

African (AFR)

AF:

0.00553

AC:

185

AN:

33466

American (AMR)

AF:

0.0119

AC:

528

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.0332

AC:

865

AN:

26082

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39608

South Asian (SAS)

AF:

0.0104

AC:

894

AN:

85856

European-Finnish (FIN)

AF:

0.0252

AC:

1344

AN:

53274

Middle Eastern (MID)

AF:

0.0206

AC:

119

AN:

5764

European-Non Finnish (NFE)

AF:

0.0384

AC:

42627

AN:

1110992

Other (OTH)

AF:

0.0276

AC:

1662

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

2174

4349

6523

8698

10872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1578

3156

4734

6312

7890

<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:

0.0248

AC:

3777

AN:

152208

Hom.:

Cov.:

AF XY:

0.0236

AC XY:

1756

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00811

AC:

337

AN:

41548

American (AMR)

AF:

0.0215

AC:

329

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0352

AC:

122

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00872

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0227

AC:

240

AN:

10582

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0386

AC:

2628

AN:

68024

Other (OTH)

AF:

0.0276

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

194

389

583

778

972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0336

Hom.:

361

Bravo

AF:

0.0240

TwinsUK

AF:

0.0378

AC:

140

ALSPAC

AF:

0.0389

AC:

150

ESP6500AA

AF:

0.00797

AC:

ESP6500EA

AF:

0.0370

AC:

305

ExAC

AF:

0.0258

AC:

3120

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 31, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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

Benign

0.22

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.074

T;T;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.94

.;.;D

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Pathogenic

3.1

M;M;M

PhyloP100

5.1

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Benign

0.19

Sift

Benign

0.033

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.16

MPC

0.043

ClinPred

0.031

GERP RS

5.7

PromoterAI

-0.065

Neutral

(source)

Varity_R

0.45

gMVP

0.18

Mutation Taster

=93/7

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