chr3-69119567-A-G

Variant names:

• chr3-69119567-A-G
• rs9835034
• NM_198271.5:c.788T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198271.5(LMOD3):​c.788T>C​(p.Ile263Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,613,792 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 9.32
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019999504).
• BP6: Variant 3-69119567-A-G is Benign according to our data. Variant chr3-69119567-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475333.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00188 (286/152274) while in subpopulation AFR AF = 0.00652 (271/41538). AF 95% confidence interval is 0.00589. There are 0 homozygotes in GnomAd4. There are 143 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.788T>C	p.Ile263Thr	missense	Exon 2 of 3	NP_938012.2
	LMOD3	NM_001304418.3		c.788T>C	p.Ile263Thr	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.788T>C	p.Ile263Thr	missense	Exon 2 of 3	ENSP00000414670.3
	LMOD3	ENST00000475434.1	TSL:5	c.788T>C	p.Ile263Thr	missense	Exon 3 of 4	ENSP00000418645.1
	LMOD3	ENST00000489031.5	TSL:2	c.788T>C	p.Ile263Thr	missense	Exon 3 of 4	ENSP00000417210.1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000538 AC: 134 AN: 248990 AF XY: 0.000429

Gnomad AFR exome AF: 0.00672

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.000373

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000228 AC: 333 AN: 1461518 Hom.: 2 Cov.: 33 AF XY: 0.000202 AC XY: 147 AN XY: 727036

African (AFR) AF: 0.00720 AC: 241 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53226

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111856

Other (OTH) AF: 0.000513 AC: 31 AN: 60374

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152274 Hom.: 0 Cov.: 31 AF XY: 0.00192 AC XY: 143 AN XY: 74456

African (AFR) AF: 0.00652 AC: 271 AN: 41538

American (AMR) AF: 0.000654 AC: 10 AN: 15298

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000620 Hom.: 1

Bravo AF: 0.00239

ESP6500AA AF: 0.00730 AC: 28

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000579 AC: 70

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 10 Uncertain:1 Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 21, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

not provided Benign:1

Mar 06, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.61
MPC		0.17
ClinPred		0.058	T
GERP RS		5.5
Varity_R		0.22
gMVP		0.65
Mutation Taster		=57/43	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: rs9835034; hg19: chr3-69168718;