rs116257053

Positions:

chr3-69119129-T-C

Variant summary

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

The NM_198271.5(LMOD3):c.1226A>G(p.Gln409Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,613,846 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 50 hom., cov: 31)

Exomes 𝑓: 0.0013 ( 33 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 8.02

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=0.006065905).

BP6

Variant 3-69119129-T-C is Benign according to our data. Variant chr3-69119129-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 475297.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 = 0.0133 (2028/152150) while in subpopulation AFR AF= 0.0451 (1871/41474). AF 95% confidence interval is 0.0434. There are 50 homozygotes in gnomad4. There are 951 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5 linkuse as main transcript	c.1226A>G	p.Gln409Arg	missense_variant	2/3	ENST00000420581.7	NP_938012.2	Q0VAK6-1
LMOD3	NM_001304418.3 linkuse as main transcript	c.1226A>G	p.Gln409Arg	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.1226A>G	p.Gln409Arg	missense_variant	2/3	1	NM_198271.5	ENSP00000414670.3	Q0VAK6-1
LMOD3	ENST00000475434.1 linkuse as main transcript	c.1226A>G	p.Gln409Arg	missense_variant	3/4	5		ENSP00000418645.1	Q0VAK6-1
LMOD3	ENST00000489031.5 linkuse as main transcript	c.1226A>G	p.Gln409Arg	missense_variant	3/4	2		ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2023

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0451

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00813

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:

0.000118

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.00327

AC:

814

AN:

249112

Hom.:

AF XY:

0.00232

AC XY:

313

AN XY:

135136

show subpopulations

Gnomad AFR exome

AF:

0.0472

Gnomad AMR exome

AF:

0.00200

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:

0.0000620

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00133

AC:

1946

AN:

1461696

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

808

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0479

Gnomad4 AMR exome

AF:

0.00246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.00321

GnomAD4 genome

AF:

0.0133

AC:

2028

AN:

152150

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

951

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0451

Gnomad4 AMR

AF:

0.00812

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00240

Hom.:

Bravo

AF:

0.0158

ESP6500AA

AF:

0.0358

AC:

140

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00399

AC:

482

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 2020	- -
Likely 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

Benign

0.19

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

.;.;T

MetaRNN

Benign

0.0061

T;T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.54

MVP

0.93

MPC

0.17

ClinPred

0.021

GERP RS

5.8

Varity_R

0.67

gMVP

0.51

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