chr3-69119929-T-G

Position:

• chr3-69119929-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000420581.7(LMOD3):​c.426A>C​(p.Glu142Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,558,826 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E142E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (16 hom.)
• Consequence: LMOD3 ENST00000420581.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.307

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004485756).
• BP6: Variant 3-69119929-T-G is Benign according to our data. Variant chr3-69119929-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 475322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00225 (342/152278) while in subpopulation NFE AF= 0.00396 (269/68014). AF 95% confidence interval is 0.00357. There are 0 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.426A>C	p.Glu142Asp	missense_variant	2/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.426A>C	p.Glu142Asp	missense_variant	3/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.426A>C	p.Glu142Asp	missense_variant	2/3	1	NM_198271.5	ENSP00000414670	P1
LMOD3	ENST00000475434.1	c.426A>C	p.Glu142Asp	missense_variant	3/4	5		ENSP00000418645	P1
LMOD3	ENST00000489031.5	c.426A>C	p.Glu142Asp	missense_variant	3/4	2		ENSP00000417210	P1

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 341 AN: 152160 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00394

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00197 AC: 337 AN: 171080 Hom.: 2 AF XY: 0.00210 AC XY: 190 AN XY: 90600

Gnomad AFR exome AF: 0.000524

Gnomad AMR exome AF: 0.000513

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00194

Gnomad FIN exome AF: 0.00146

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00337 AC: 4739 AN: 1406548 Hom.: 16 Cov.: 30 AF XY: 0.00333 AC XY: 2313 AN XY: 695046

Gnomad4 AFR exome AF: 0.000655

Gnomad4 AMR exome AF: 0.000442

Gnomad4 ASJ exome AF: 0.0000792

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00399

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00225 AC: 342 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.00215 AC XY: 160 AN XY: 74472

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00396

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00223 Hom.: 2

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00415 AC: 16

ExAC AF: 0.00120 AC: 139

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	LMOD3: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2020	This variant is associated with the following publications: (PMID: 29923248) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 06, 2020

- -

LMOD3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	0.078
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T;T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.46	.;.;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.9	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.070	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.075
MutPred		0.44		Gain of glycosylation at S137 (P = 0.0035);Gain of glycosylation at S137 (P = 0.0035);Gain of glycosylation at S137 (P = 0.0035);
MVP		0.79
MPC		0.020
ClinPred		0.0014	T
GERP RS		1.3
Varity_R		0.082
gMVP		0.035

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

Other links and lift over

dbSNP: rs111848977; hg19: chr3-69169080;