NM_198271.5:c.426A>C

Variant names:

• chr3-69119929-T-G
• rs111848977
• NM_198271.5:c.426A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198271.5(LMOD3):​c.426A>C​(p.Glu142Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,558,826 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E142E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (16 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.307
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004485756).
• BP6: Variant 3-69119929-T-G is Benign according to our data. Variant chr3-69119929-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475322.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 = 0.00225 (342/152278) while in subpopulation NFE AF = 0.00396 (269/68014). AF 95% confidence interval is 0.00357. There are 0 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 16 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.426A>C	p.Glu142Asp	missense	Exon 2 of 3	NP_938012.2
	LMOD3	NM_001304418.3		c.426A>C	p.Glu142Asp	missense	Exon 3 of 4	NP_001291347.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	ENST00000420581.7	TSL:1 MANE Select	c.426A>C	p.Glu142Asp	missense	Exon 2 of 3	ENSP00000414670.3
	LMOD3	ENST00000475434.1	TSL:5	c.426A>C	p.Glu142Asp	missense	Exon 3 of 4	ENSP00000418645.1
	LMOD3	ENST00000489031.5	TSL:2	c.426A>C	p.Glu142Asp	missense	Exon 3 of 4	ENSP00000417210.1

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 341 AN: 152160 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00394

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00197 AC: 337 AN: 171080 AF XY: 0.00210

Gnomad AFR exome AF: 0.000524

Gnomad AMR exome AF: 0.000513

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00146

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00337 AC: 4739 AN: 1406548 Hom.: 16 Cov.: 30 AF XY: 0.00333 AC XY: 2313 AN XY: 695046

African (AFR) AF: 0.000655 AC: 21 AN: 32066

American (AMR) AF: 0.000442 AC: 16 AN: 36222

Ashkenazi Jewish (ASJ) AF: 0.0000792 AC: 2 AN: 25240

East Asian (EAS) AF: 0.00 AC: 0 AN: 36800

South Asian (SAS) AF: 0.00165 AC: 133 AN: 80622

European-Finnish (FIN) AF: 0.00155 AC: 78 AN: 50386

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5702

European-Non Finnish (NFE) AF: 0.00399 AC: 4309 AN: 1081136

Other (OTH) AF: 0.00295 AC: 172 AN: 58374

GnomAD4 genome AF: 0.00225 AC: 342 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.00215 AC XY: 160 AN XY: 74472

African (AFR) AF: 0.000962 AC: 40 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4832

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00396 AC: 269 AN: 68014

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00898 Hom.: 9

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00415 AC: 16

ExAC AF: 0.00120 AC: 139

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 06, 2020

GeneDx

Significance: Likely 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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LMOD3: BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

May 06, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nemaline myopathy 10 Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LMOD3-related disorder Benign:1

Jul 19, 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	0.078
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.31
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Benign	0.070	T
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.075
MutPred		0.44		Gain of glycosylation at S137 (P = 0.0035)
MVP		0.79
MPC		0.020
ClinPred		0.0014	T
GERP RS		1.3
Varity_R		0.082
gMVP		0.035
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs111848977; hg19: chr3-69169080;