rs75713718

Positions:

• chr3-69119098-C-G

Variant summary

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

The NM_198271.5(LMOD3):​c.1257G>C​(p.Met419Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000677 in 1,613,846 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00038 (4 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.70

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=0.008024842).
• BP6: Variant 3-69119098-C-G is Benign according to our data. Variant chr3-69119098-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 475298.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 = 0.00352 (536/152142) while in subpopulation AFR AF= 0.0124 (513/41482). AF 95% confidence interval is 0.0115. There are 1 homozygotes in gnomad4. There are 259 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.1257G>C	p.Met419Ile	missense_variant	2/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.1257G>C	p.Met419Ile	missense_variant	3/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.1257G>C	p.Met419Ile	missense_variant	2/3	1	NM_198271.5	ENSP00000414670	P1
LMOD3	ENST00000475434.1	c.1257G>C	p.Met419Ile	missense_variant	3/4	5		ENSP00000418645	P1
LMOD3	ENST00000489031.5	c.1257G>C	p.Met419Ile	missense_variant	3/4	2		ENSP00000417210	P1

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 527 AN: 152024 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000827 AC: 206 AN: 249146 Hom.: 1 AF XY: 0.000644 AC XY: 87 AN XY: 135164

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000381 AC: 557 AN: 1461704 Hom.: 4 Cov.: 33 AF XY: 0.000338 AC XY: 246 AN XY: 727132

Gnomad4 AFR exome AF: 0.0125

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152142 Hom.: 1 Cov.: 31 AF XY: 0.00348 AC XY: 259 AN XY: 74392

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000644 Hom.: 0

Bravo AF: 0.00399

ESP6500AA AF: 0.0124 AC: 48

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000935 AC: 113

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	LMOD3: BS1 -

Nemaline myopathy 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T;T;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	.;.;T
MetaRNN	Benign	0.0080	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.074
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.22	T;T;T
Polyphen		0.98	D;D;D
Vest4		0.52
MutPred		0.38		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.21
MPC		0.14
ClinPred		0.040	T
GERP RS		5.8
Varity_R		0.55
gMVP		0.43

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: rs75713718; hg19: chr3-69168249;