3-69122139-C-T

Position:

chr3-69122139-C-T

Variant summary

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

The ENST00000420581.7(LMOD3):c.248G>A(p.Arg83His) variant causes a missense change. The variant allele was found at a frequency of 0.0323 in 1,612,120 control chromosomes in the GnomAD database, including 980 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R83C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.025 ( 58 hom., cov: 32)

Exomes 𝑓: 0.033 ( 922 hom. )

Consequence

LMOD3
ENST00000420581.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.06

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=0.004994124).

BP6

Variant 3-69122139-C-T is Benign according to our data. Variant chr3-69122139-C-T is described in ClinVar as [Benign]. Clinvar id is 475315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69122139-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0248 (3777/152208) while in subpopulation NFE AF= 0.0386 (2628/68024). AF 95% confidence interval is 0.0374. There are 58 homozygotes in gnomad4. There are 1756 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5 linkuse as main transcript	c.248G>A	p.Arg83His	missense_variant	1/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3 linkuse as main transcript	c.248G>A	p.Arg83His	missense_variant	2/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7 linkuse as main transcript	c.248G>A	p.Arg83His	missense_variant	1/3	1	NM_198271.5	ENSP00000414670	P1	Q0VAK6-1
LMOD3	ENST00000475434.1 linkuse as main transcript	c.248G>A	p.Arg83His	missense_variant	2/4	5		ENSP00000418645	P1	Q0VAK6-1
LMOD3	ENST00000489031.5 linkuse as main transcript	c.248G>A	p.Arg83His	missense_variant	2/4	2		ENSP00000417210	P1	Q0VAK6-1

Frequencies

GnomAD3 genomes

AF:

0.0248

AC:

3778

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00813

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0216

Gnomad ASJ

AF:

0.0352

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00892

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0386

Gnomad OTH

AF:

0.0279

GnomAD3 exomes

AF:

0.0253

AC:

6218

AN:

246150

Hom.:

111

AF XY:

0.0252

AC XY:

3362

AN XY:

133400

show subpopulations

Gnomad AFR exome

AF:

0.00643

Gnomad AMR exome

AF:

0.0114

Gnomad ASJ exome

AF:

0.0355

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0113

Gnomad FIN exome

AF:

0.0253

Gnomad NFE exome

AF:

0.0390

Gnomad OTH exome

AF:

0.0253

GnomAD4 exome

AF:

0.0330

AC:

48225

AN:

1459912

Hom.:

922

Cov.:

AF XY:

0.0323

AC XY:

23479

AN XY:

726026

show subpopulations

Gnomad4 AFR exome

AF:

0.00553

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.0332

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0104

Gnomad4 FIN exome

AF:

0.0252

Gnomad4 NFE exome

AF:

0.0384

Gnomad4 OTH exome

AF:

0.0276

GnomAD4 genome

AF:

0.0248

AC:

3777

AN:

152208

Hom.:

Cov.:

AF XY:

0.0236

AC XY:

1756

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00811

Gnomad4 AMR

AF:

0.0215

Gnomad4 ASJ

AF:

0.0352

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00872

Gnomad4 FIN

AF:

0.0227

Gnomad4 NFE

AF:

0.0386

Gnomad4 OTH

AF:

0.0276

Alfa

AF:

0.0346

Hom.:

191

Bravo

AF:

0.0240

TwinsUK

AF:

0.0378

AC:

140

ALSPAC

AF:

0.0389

AC:

150

ESP6500AA

AF:

0.00797

AC:

ESP6500EA

AF:

0.0370

AC:

305

ExAC

AF:

0.0258

AC:

3120

Asia WGS

AF:

0.00549

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2019	This variant is associated with the following publications: (PMID: 29923248) -

Nemaline myopathy 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.074

T;T;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.94

.;.;D

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Pathogenic

3.1

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Benign

0.19

Sift

Benign

0.033

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.16

MPC

0.043

ClinPred

0.031

GERP RS

5.7

Varity_R

0.45

gMVP

0.18

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