rs752432695

Positions:

• chr3-69122184-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198271.5(LMOD3):​c.203A>G​(p.His68Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.203A>G	p.His68Arg	missense_variant	1/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.203A>G	p.His68Arg	missense_variant	2/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.203A>G	p.His68Arg	missense_variant	1/3	1	NM_198271.5	ENSP00000414670.3
LMOD3	ENST00000475434.1	c.203A>G	p.His68Arg	missense_variant	2/4	5		ENSP00000418645.1
LMOD3	ENST00000489031.5	c.203A>G	p.His68Arg	missense_variant	2/4	2		ENSP00000417210.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247760 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134416

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 23, 2018

This sequence change replaces histidine with arginine at codon 68 of the LMOD3 protein (p.His68Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs752432695, ExAC 0.002%). This variant has not been reported in the literature in individuals with LMOD3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.0080	T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	.;.;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L;L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.15	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.69	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.98	D;D;D
Vest4		0.56
MutPred		0.35		Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);
MVP		0.29
MPC		0.18
ClinPred		0.83	D
GERP RS		5.7
Varity_R		0.27
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752432695; hg19: chr3-69171335;