3-69122139-C-A

Variant names:

• chr3-69122139-C-A
• rs35740823
• NM_198271.5:c.248G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198271.5(LMOD3):​c.248G>T​(p.Arg83Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.06
• Publications: 9 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: ClinGen, Labcorp Genetics (formerly Invitae), 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	NM_198271.5	MANE Select	c.248G>T	p.Arg83Leu	missense	Exon 1 of 3	NP_938012.2	Q0VAK6-1
	LMOD3	NM_001304418.3		c.248G>T	p.Arg83Leu	missense	Exon 2 of 4	NP_001291347.1	Q0VAK6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	ENST00000420581.7	TSL:1 MANE Select	c.248G>T	p.Arg83Leu	missense	Exon 1 of 3	ENSP00000414670.3	Q0VAK6-1
	LMOD3	ENST00000475434.1	TSL:5	c.248G>T	p.Arg83Leu	missense	Exon 2 of 4	ENSP00000418645.1	Q0VAK6-1
	LMOD3	ENST00000489031.5	TSL:2	c.248G>T	p.Arg83Leu	missense	Exon 2 of 4	ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246150 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000564

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.4	D
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.48		Gain of glycosylation at S81 (P = 0.0162)
MVP		0.54
MPC		0.16
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		-0.069	Neutral
Varity_R		0.74
gMVP		0.31
Mutation Taster		=76/24	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: rs35740823; hg19: chr3-69171290;