rs150380359

chr3-69119939-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_198271.5(LMOD3):c.416A>G(p.Asn139Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,564,196 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N139N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.0890

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.004740447).

BP6

Variant 3-69119939-T-C is Benign according to our data. Variant chr3-69119939-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475321.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000479 (73/152308) while in subpopulation AFR AF= 0.00156 (65/41580). AF 95% confidence interval is 0.00126. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMOD3	NM_198271.5 linkuse as main transcript	c.416A>G	p.Asn139Ser	missense_variant	2/3	ENST00000420581.7
LMOD3	NM_001304418.3 linkuse as main transcript	c.416A>G	p.Asn139Ser	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMOD3	ENST00000420581.7 linkuse as main transcript	c.416A>G	p.Asn139Ser	missense_variant	2/3	1	NM_198271.5	P1	Q0VAK6-1
LMOD3	ENST00000475434.1 linkuse as main transcript	c.416A>G	p.Asn139Ser	missense_variant	3/4	5		P1	Q0VAK6-1
LMOD3	ENST00000489031.5 linkuse as main transcript	c.416A>G	p.Asn139Ser	missense_variant	3/4	2		P1	Q0VAK6-1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000226

AC:

AN:

176928

Hom.:

AF XY:

0.000159

AC XY:

AN XY:

94104

show subpopulations

Gnomad AFR exome

AF:

0.00288

Gnomad AMR exome

AF:

0.000194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000696

Gnomad OTH exome

AF:

0.000208

GnomAD4 exome

AF:

0.000194

AC:

274

AN:

1411888

Hom.:

Cov.:

AF XY:

0.000195

AC XY:

136

AN XY:

698078

show subpopulations

Gnomad4 AFR exome

AF:

0.00211

Gnomad4 AMR exome

AF:

0.000219

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000168

Gnomad4 OTH exome

AF:

0.000273

GnomAD4 genome

AF:

0.000479

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000442

Hom.:

Bravo

AF:

0.000767

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00153

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.000128

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.416A>G (p.N139S) alteration is located in exon 2 (coding exon 2) of the LMOD3 gene. This alteration results from a A to G substitution at nucleotide position 416, causing the asparagine (N) at amino acid position 139 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Nemaline myopathy 10

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

LMOD3-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

Cadd

Benign

0.42

Dann

Benign

0.34

DEOGEN2

Benign

0.0044

T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.10

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.0047

T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.2

L;L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.77

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.56

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.084

MVP

0.35

MPC

0.019

ClinPred

0.020

GERP RS

-6.7

Varity_R

0.038

gMVP

0.027

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over