NM_198271.5:c.476delG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_198271.5(LMOD3):c.476delG(p.Gly159GlufsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

LMOD3
NM_198271.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.0230

Publications

1 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
typical nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe congenital nemaline myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LMOD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-69119878-TC-T is Pathogenic according to our data. Variant chr3-69119878-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 475328.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMOD3	NM_198271.5 link	c.476delG	p.Gly159GlufsTer33	frameshift_variant	Exon 2 of 3	ENST00000420581.7	NP_938012.2	Q0VAK6-1
LMOD3	NM_001304418.3 link	c.476delG	p.Gly159GlufsTer33	frameshift_variant	Exon 3 of 4		NP_001291347.1	Q0VAK6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LMOD3	ENST00000420581.7 link	c.476delG	p.Gly159GlufsTer33	frameshift_variant	Exon 2 of 3	1	NM_198271.5	ENSP00000414670.3	Q0VAK6-1
LMOD3	ENST00000475434.1 link	c.476delG	p.Gly159GlufsTer33	frameshift_variant	Exon 3 of 4	5		ENSP00000418645.1	Q0VAK6-1
LMOD3	ENST00000489031.5 link	c.476delG	p.Gly159GlufsTer33	frameshift_variant	Exon 3 of 4	2		ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000606

AC:

AN:

165132

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000400

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1399702

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691402

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31740

American (AMR)

AF:

0.0000279

AC:

AN:

35900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25192

East Asian (EAS)

AF:

0.00

AC:

AN:

36134

South Asian (SAS)

AF:

0.00

AC:

AN:

80096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49986

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1076798

Other (OTH)

AF:

0.00

AC:

AN:

58160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nemaline myopathy 10

Pathogenic:1

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with LMOD3-related conditions. ClinVar contains an entry for this variant (Variation ID: 475328). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gly159Glufs*33) in the LMOD3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMOD3 are known to be pathogenic (PMID: 25250574). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.023

Mutation Taster

=43/157

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over