3-69109096-T-TA

Position:

• chr3-69109096-T-TA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The ENST00000420581.7(LMOD3):​c.1681_1682insT​(p.Ter561LeufsTer8) variant causes a frameshift, stop lost change. The variant allele was found at a frequency of 0.00000207 in 1,448,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LMOD3 ENST00000420581.7 frameshift, stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.34

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
• PM4: Stoplost variant in ENST00000420581.7 Downstream stopcodon found after 63 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.1681_1682insT	p.Ter561LeufsTer8	frameshift_variant, stop_lost	3/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.1681_1682insT	p.Ter561LeufsTer8	frameshift_variant, stop_lost	4/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.1681_1682insT	p.Ter561LeufsTer8	frameshift_variant, stop_lost	3/3	1	NM_198271.5	ENSP00000414670	P1
LMOD3	ENST00000475434.1	c.1681_1682insT	p.Ter561LeufsTer8	frameshift_variant, stop_lost	4/4	5		ENSP00000418645	P1
LMOD3	ENST00000489031.5	c.1681_1682insT	p.Ter561LeufsTer8	frameshift_variant, stop_lost	4/4	2		ENSP00000417210	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448518 Hom.: 0 Cov.: 29 AF XY: 0.00000417 AC XY: 3 AN XY: 719032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Sep 18, 2018

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. This variant has not been reported in the literature in individuals with LMOD3-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change disrupts the translational stop signal of the LMOD3 mRNA. It is expected to extend the length of the LMOD3 protein by 7 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1575869958; hg19: chr3-69158247;