rs74350755

Positions:

chr3-69119211-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_198271.5(LMOD3):c.1144C>T(p.Pro382Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,864 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 17 hom., cov: 31)

Exomes 𝑓: 0.00073 ( 10 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 10.0

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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.021602124).

BP6

Variant 3-69119211-G-A is Benign according to our data. Variant chr3-69119211-G-A is described in ClinVar as [Benign]. Clinvar id is 475296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00753 (1146/152168) while in subpopulation AFR AF= 0.0247 (1026/41492). AF 95% confidence interval is 0.0235. There are 17 homozygotes in gnomad4. There are 522 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5 linkuse as main transcript	c.1144C>T	p.Pro382Ser	missense_variant	2/3	ENST00000420581.7	NP_938012.2	Q0VAK6-1
LMOD3	NM_001304418.3 linkuse as main transcript	c.1144C>T	p.Pro382Ser	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.1144C>T	p.Pro382Ser	missense_variant	2/3	1	NM_198271.5	ENSP00000414670.3	Q0VAK6-1
LMOD3	ENST00000475434.1 linkuse as main transcript	c.1144C>T	p.Pro382Ser	missense_variant	3/4	5		ENSP00000418645.1	Q0VAK6-1
LMOD3	ENST00000489031.5 linkuse as main transcript	c.1144C>T	p.Pro382Ser	missense_variant	3/4	2		ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes

AF:

0.00752

AC:

1143

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00648

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:

0.0000588

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00182

AC:

454

AN:

248966

Hom.:

AF XY:

0.00131

AC XY:

177

AN XY:

135048

show subpopulations

Gnomad AFR exome

AF:

0.0251

Gnomad AMR exome

AF:

0.00151

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:

0.0000621

Gnomad OTH exome

AF:

0.000993

GnomAD4 exome

AF:

0.000731

AC:

1069

AN:

1461696

Hom.:

Cov.:

AF XY:

0.000616

AC XY:

448

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0253

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00199

GnomAD4 genome

AF:

0.00753

AC:

1146

AN:

152168

Hom.:

Cov.:

AF XY:

0.00702

AC XY:

522

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0247

Gnomad4 AMR

AF:

0.00648

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00125

Hom.:

Bravo

AF:

0.00901

ESP6500AA

AF:

0.0189

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00216

AC:

261

Asia WGS

AF:

0.000577

AC:

AN:

3478

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	Jan 09, 2020	- -
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 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

T;T;T

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

.;.;D

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.5

D;D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.85

MVP

0.99

MPC

0.17

ClinPred

0.048

GERP RS

5.8

Varity_R

0.67

gMVP

0.66

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