rs199592188

Positions:

• chr3-69119165-T-A
• chr3-69119165-T-C

Variant summary

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

The NM_198271.5(LMOD3):​c.1190A>T​(p.Gln397Leu) 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.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.26

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.1190A>T	p.Gln397Leu	missense_variant	2/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.1190A>T	p.Gln397Leu	missense_variant	3/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.1190A>T	p.Gln397Leu	missense_variant	2/3	1	NM_198271.5	ENSP00000414670	P1
LMOD3	ENST00000475434.1	c.1190A>T	p.Gln397Leu	missense_variant	3/4	5		ENSP00000418645	P1
LMOD3	ENST00000489031.5	c.1190A>T	p.Gln397Leu	missense_variant	3/4	2		ENSP00000417210	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Uncertain	0.61
Sift	Benign	0.055	T;T;T
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.93	P;P;P
Vest4		0.57
MutPred		0.35		Loss of glycosylation at K400 (P = 0.0716);Loss of glycosylation at K400 (P = 0.0716);Loss of glycosylation at K400 (P = 0.0716);
MVP		0.94
MPC		0.078
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.33
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs199592188; hg19: chr3-69168316;