chr3-69119567-A-G

Position:

chr3-69119567-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198271.5(LMOD3):c.788T>C(p.Ile263Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,613,792 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

LMOD3
NM_198271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 9.32

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019999504).

BP6

Variant 3-69119567-A-G is Benign according to our data. Variant chr3-69119567-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475333.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr3-69119567-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00188 (286/152274) while in subpopulation AFR AF= 0.00652 (271/41538). AF 95% confidence interval is 0.00589. There are 0 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5 linkuse as main transcript	c.788T>C	p.Ile263Thr	missense_variant	2/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3 linkuse as main transcript	c.788T>C	p.Ile263Thr	missense_variant	3/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7 linkuse as main transcript	c.788T>C	p.Ile263Thr	missense_variant	2/3	1	NM_198271.5	ENSP00000414670	P1	Q0VAK6-1
LMOD3	ENST00000475434.1 linkuse as main transcript	c.788T>C	p.Ile263Thr	missense_variant	3/4	5		ENSP00000418645	P1	Q0VAK6-1
LMOD3	ENST00000489031.5 linkuse as main transcript	c.788T>C	p.Ile263Thr	missense_variant	3/4	2		ENSP00000417210	P1	Q0VAK6-1

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

285

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000538

AC:

134

AN:

248990

Hom.:

AF XY:

0.000429

AC XY:

AN XY:

135088

show subpopulations

Gnomad AFR exome

AF:

0.00672

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000373

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000228

AC:

333

AN:

1461518

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.00720

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.00188

AC:

286

AN:

152274

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00652

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000412

Hom.:

Bravo

AF:

0.00239

ESP6500AA

AF:

0.00730

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000579

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 10

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

T;T;T

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Pathogenic

3.4

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.4

N;N;N

REVEL

Uncertain

0.50

Sift

Uncertain

0.011

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.80

MVP

0.61

MPC

0.17

ClinPred

0.058

GERP RS

5.5

Varity_R

0.22

gMVP

0.65

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