3-69119165-T-C

Position:

chr3-69119165-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198271.5(LMOD3):c.1190A>G(p.Gln397Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00211 in 1,613,880 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0022 ( 6 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 6.26

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013280481).

BP6

Variant 3-69119165-T-C is Benign according to our data. Variant chr3-69119165-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475293.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00151 (230/152204) while in subpopulation NFE AF= 0.00257 (175/68002). AF 95% confidence interval is 0.00226. There are 1 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5 linkuse as main transcript	c.1190A>G	p.Gln397Arg	missense_variant	2/3	ENST00000420581.7	NP_938012.2	Q0VAK6-1
LMOD3	NM_001304418.3 linkuse as main transcript	c.1190A>G	p.Gln397Arg	missense_variant	3/4		NP_001291347.1	Q0VAK6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LMOD3	ENST00000420581.7 linkuse as main transcript	c.1190A>G	p.Gln397Arg	missense_variant	2/3	1	NM_198271.5	ENSP00000414670.3	Q0VAK6-1
LMOD3	ENST00000475434.1 linkuse as main transcript	c.1190A>G	p.Gln397Arg	missense_variant	3/4	5		ENSP00000418645.1	Q0VAK6-1
LMOD3	ENST00000489031.5 linkuse as main transcript	c.1190A>G	p.Gln397Arg	missense_variant	3/4	2		ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes

AF:

0.00151

AC:

230

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00257

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00169

AC:

421

AN:

249000

Hom.:

AF XY:

0.00173

AC XY:

234

AN XY:

135064

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00223

Gnomad NFE exome

AF:

0.00307

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00218

AC:

3180

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

1553

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00230

Gnomad4 NFE exome

AF:

0.00264

Gnomad4 OTH exome

AF:

0.00161

GnomAD4 genome

AF:

0.00151

AC:

230

AN:

152204

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

119

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00257

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00225

Hom.:

Bravo

AF:

0.00163

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000776

AC:

ESP6500EA

AF:

0.00265

AC:

ExAC

AF:

0.00187

AC:

226

EpiCase

AF:

0.00213

EpiControl

AF:

0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2021	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.1190A>G (p.Q397R) 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 1190, causing the glutamine (Q) at amino acid position 397 to be replaced by an arginine (R). 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

LMOD3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2022

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

0.18

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

T;T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.049

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.74

.;.;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Uncertain

-0.079

MutationAssessor

Benign

1.6

L;L;L

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Uncertain

0.31

Sift

Benign

0.21

T;T;T

Sift4G

Uncertain

0.059

T;T;T

Polyphen

0.027

B;B;B

Vest4

0.25

MVP

0.88

MPC

0.022

ClinPred

0.043

GERP RS

4.3

Varity_R

0.28

gMVP

0.47

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