3-69109111-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198271.5(LMOD3):c.1667C>A(p.Pro556Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000711 in 1,602,286 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P556R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00074 ( 6 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 6.79

Publications

2 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009101003).

BP6

Variant 3-69109111-G-T is Benign according to our data. Variant chr3-69109111-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 218866. Variant chr3-69109111-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 218866. Variant chr3-69109111-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 218866. Variant chr3-69109111-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 218866. Variant chr3-69109111-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 218866. Variant chr3-69109111-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 218866.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00048 (73/152108) while in subpopulation SAS AF = 0.00705 (34/4820). AF 95% confidence interval is 0.00519. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMOD3	NM_198271.5 link	c.1667C>A	p.Pro556Gln	missense_variant	Exon 3 of 3	ENST00000420581.7	NP_938012.2	Q0VAK6-1
LMOD3	NM_001304418.3 link	c.1667C>A	p.Pro556Gln	missense_variant	Exon 4 of 4		NP_001291347.1	Q0VAK6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LMOD3	ENST00000420581.7 link	c.1667C>A	p.Pro556Gln	missense_variant	Exon 3 of 3	1	NM_198271.5	ENSP00000414670.3	Q0VAK6-1
LMOD3	ENST00000475434.1 link	c.1667C>A	p.Pro556Gln	missense_variant	Exon 4 of 4	5		ENSP00000418645.1	Q0VAK6-1
LMOD3	ENST00000489031.5 link	c.1667C>A	p.Pro556Gln	missense_variant	Exon 4 of 4	2		ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes

AF:

0.000487

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00726

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00110

AC:

251

AN:

227842

AF XY:

0.00138

show subpopulations

Gnomad AFR exome

AF:

0.0000709

Gnomad AMR exome

AF:

0.000245

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000534

Gnomad OTH exome

AF:

0.000705

GnomAD4 exome

AF:

0.000736

AC:

1067

AN:

1450178

Hom.:

Cov.:

AF XY:

0.000928

AC XY:

668

AN XY:

720012

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33356

American (AMR)

AF:

0.000208

AC:

AN:

43248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25872

East Asian (EAS)

AF:

0.00

AC:

AN:

39378

South Asian (SAS)

AF:

0.00733

AC:

614

AN:

83790

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52530

Middle Eastern (MID)

AF:

0.00383

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000325

AC:

360

AN:

1106258

Other (OTH)

AF:

0.00102

AC:

AN:

60002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.000480

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41484

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00705

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68010

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000559

Hom.:

Bravo

AF:

0.000363

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000267

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.00112

AC:

135

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 10

Benign:2

Dec 29, 2023

Revvity Omics, Revvity

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Apr 12, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LMOD3: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.054

T;T;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.63

.;.;T

MetaRNN

Benign

0.0091

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;L

PhyloP100

6.8

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.6

D;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.045

D;D;D

Polyphen

0.62

P;P;P

Vest4

0.75

MVP

0.44

MPC

0.081

ClinPred

0.12

GERP RS

5.5

Varity_R

0.59

gMVP

0.40

Mutation Taster

=75/25

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over