3-69119567-A-T

Position:

• chr3-69119567-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198271.5(LMOD3):​c.788T>A​(p.Ile263Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. I263T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.788T>A	p.Ile263Asn	missense_variant	2/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.788T>A	p.Ile263Asn	missense_variant	3/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.788T>A	p.Ile263Asn	missense_variant	2/3	1	NM_198271.5	ENSP00000414670.3
LMOD3	ENST00000475434.1	c.788T>A	p.Ile263Asn	missense_variant	3/4	5		ENSP00000418645.1
LMOD3	ENST00000489031.5	c.788T>A	p.Ile263Asn	missense_variant	3/4	2		ENSP00000417210.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.4	M;M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.86
MutPred		0.55		Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);
MVP		0.68
MPC		0.19
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.57
gMVP		0.74

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: rs9835034; hg19: chr3-69168718;