rs111797345

Positions:

chr3-69119477-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198271.5(LMOD3):c.878G>A(p.Gly293Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,613,904 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 36 hom., cov: 31)

Exomes 𝑓: 0.019 ( 367 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.91

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010550827).

BP6

Variant 3-69119477-C-T is Benign according to our data. Variant chr3-69119477-C-T is described in ClinVar as [Benign]. Clinvar id is 475334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69119477-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0151 (2293/152242) while in subpopulation NFE AF= 0.0179 (1218/68008). AF 95% confidence interval is 0.0171. There are 36 homozygotes in gnomad4. There are 1248 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5 linkuse as main transcript	c.878G>A	p.Gly293Asp	missense_variant	2/3	ENST00000420581.7	NP_938012.2	Q0VAK6-1
LMOD3	NM_001304418.3 linkuse as main transcript	c.878G>A	p.Gly293Asp	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.878G>A	p.Gly293Asp	missense_variant	2/3	1	NM_198271.5	ENSP00000414670.3	Q0VAK6-1
LMOD3	ENST00000475434.1 linkuse as main transcript	c.878G>A	p.Gly293Asp	missense_variant	3/4	5		ENSP00000418645.1	Q0VAK6-1
LMOD3	ENST00000489031.5 linkuse as main transcript	c.878G>A	p.Gly293Asp	missense_variant	3/4	2		ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes

AF:

0.0151

AC:

2295

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.0636

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.0169

AC:

4201

AN:

248974

Hom.:

AF XY:

0.0176

AC XY:

2373

AN XY:

135048

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.00863

Gnomad ASJ exome

AF:

0.00925

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0142

Gnomad FIN exome

AF:

0.0625

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0179

GnomAD4 exome

AF:

0.0189

AC:

27582

AN:

1461662

Hom.:

367

Cov.:

AF XY:

0.0188

AC XY:

13670

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.00892

Gnomad4 ASJ exome

AF:

0.00792

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0151

Gnomad4 FIN exome

AF:

0.0563

Gnomad4 NFE exome

AF:

0.0192

Gnomad4 OTH exome

AF:

0.0194

GnomAD4 genome

AF:

0.0151

AC:

2293

AN:

152242

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1248

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00315

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0139

Gnomad4 FIN

AF:

0.0636

Gnomad4 NFE

AF:

0.0179

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0155

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.0156

AC:

ALSPAC

AF:

0.0223

AC:

ESP6500AA

AF:

0.00323

AC:

ESP6500EA

AF:

0.0189

AC:

158

ExAC

AF:

0.0154

AC:

1867

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0172

EpiControl

AF:

0.0169

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nemaline myopathy 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

T;T;T

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;.;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

3.2

M;M;M

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.62

Sift

Uncertain

0.028

D;D;D

Sift4G

Benign

0.43

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.36

MPC

0.18

ClinPred

0.027

GERP RS

5.7

Varity_R

0.32

gMVP

0.70

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