rs145387235

Positions:

chr3-69118700-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_198271.5(LMOD3):c.1655C>A(p.Pro552His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,610,364 control chromosomes in the GnomAD database, including 285 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 23 hom., cov: 30)

Exomes 𝑓: 0.017 ( 262 hom. )

Consequence

LMOD3
NM_198271.5 missense, splice_region

Scores

Splicing: ADA: 0.9584

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 9.47

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 -15 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 3-69118700-G-T is Benign according to our data. Variant chr3-69118700-G-T is described in ClinVar as [Benign]. Clinvar id is 475310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69118700-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.013 (1968/151808) while in subpopulation NFE AF= 0.0192 (1304/67942). AF 95% confidence interval is 0.0183. There are 23 homozygotes in gnomad4. There are 922 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5 linkuse as main transcript	c.1655C>A	p.Pro552His	missense_variant, splice_region_variant	2/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3 linkuse as main transcript	c.1655C>A	p.Pro552His	missense_variant, splice_region_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.1655C>A	p.Pro552His	missense_variant, splice_region_variant	2/3	1	NM_198271.5	ENSP00000414670	P1	Q0VAK6-1
LMOD3	ENST00000475434.1 linkuse as main transcript	c.1655C>A	p.Pro552His	missense_variant, splice_region_variant	3/4	5		ENSP00000418645	P1	Q0VAK6-1
LMOD3	ENST00000489031.5 linkuse as main transcript	c.1655C>A	p.Pro552His	missense_variant, splice_region_variant	3/4	2		ENSP00000417210	P1	Q0VAK6-1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1969

AN:

151690

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00439

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0162

Gnomad ASJ

AF:

0.00837

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00105

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0192

Gnomad OTH

AF:

0.0188

GnomAD3 exomes

AF:

0.0124

AC:

3057

AN:

246034

Hom.:

AF XY:

0.0123

AC XY:

1641

AN XY:

133592

show subpopulations

Gnomad AFR exome

AF:

0.00385

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.00801

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00188

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.0179

Gnomad OTH exome

AF:

0.0166

GnomAD4 exome

AF:

0.0174

AC:

25410

AN:

1458556

Hom.:

262

Cov.:

AF XY:

0.0169

AC XY:

12247

AN XY:

725406

show subpopulations

Gnomad4 AFR exome

AF:

0.00330

Gnomad4 AMR exome

AF:

0.0141

Gnomad4 ASJ exome

AF:

0.00767

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00178

Gnomad4 FIN exome

AF:

0.0157

Gnomad4 NFE exome

AF:

0.0202

Gnomad4 OTH exome

AF:

0.0160

GnomAD4 genome

AF:

0.0130

AC:

1968

AN:

151808

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

922

AN XY:

74154

show subpopulations

Gnomad4 AFR

AF:

0.00435

Gnomad4 AMR

AF:

0.0162

Gnomad4 ASJ

AF:

0.00837

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00105

Gnomad4 FIN

AF:

0.0148

Gnomad4 NFE

AF:

0.0192

Gnomad4 OTH

AF:

0.0186

Alfa

AF:

0.0177

Hom.:

Bravo

AF:

0.0131

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0195

AC:

ESP6500AA

AF:

0.00461

AC:

ESP6500EA

AF:

0.0169

AC:

140

ExAC

AF:

0.0118

AC:

1423

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2019	This variant is associated with the following publications: (PMID: 29923248) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LMOD3: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nemaline myopathy 10

Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 1.729% (rs145387235, 2288/126934 alleles, 23 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

T;T;T

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.81

.;.;T

MetaRNN

Benign

0.0071

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.8

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.94

N;N;N

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;D;D

Sift4G

Benign

0.11

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.22

MPC

0.17

ClinPred

0.018

GERP RS

5.8

Varity_R

0.37

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.74

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