dbSNP rs745318870: LMOD3:p.Val487Gly (chr3-69118895-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198271.5(LMOD3):c.1460T>G(p.Val487Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.40

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08492237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMOD3	NM_198271.5 link	c.1460T>G	p.Val487Gly	missense_variant	Exon 2 of 3	ENST00000420581.7	NP_938012.2	Q0VAK6-1
LMOD3	NM_001304418.3 link	c.1460T>G	p.Val487Gly	missense_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.1460T>G	p.Val487Gly	missense_variant	Exon 2 of 3	1	NM_198271.5	ENSP00000414670.3	Q0VAK6-1
LMOD3	ENST00000475434.1 link	c.1460T>G	p.Val487Gly	missense_variant	Exon 3 of 4	5		ENSP00000418645.1	Q0VAK6-1
LMOD3	ENST00000489031.5 link	c.1460T>G	p.Val487Gly	missense_variant	Exon 3 of 4	2		ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461614

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727084

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.0082

T;T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.35

.;.;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.085

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;L

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.033

Sift

Benign

0.089

T;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.16

MutPred

0.23

Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);Loss of stability (P = 2e-04);

MVP

0.13

MPC

0.022

ClinPred

0.27

GERP RS

3.4

Varity_R

0.15

gMVP

0.49

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over