NM_198271.5:c.39_41delTCT

Variant names:

• chr3-69122345-GAGA-G
• rs139192915
• NM_198271.5:c.39_41delTCT

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_198271.5(LMOD3):​c.39_41delTCT​(p.Leu14del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,610,784 control chromosomes in the GnomAD database, including 615 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (49 hom., cov: 32)
  • Exomes 𝑓: 0.026 (566 hom.)
• Consequence: LMOD3 NM_198271.5 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.01

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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_198271.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 3-69122345-GAGA-G is Benign according to our data. Variant chr3-69122345-GAGA-G is described in ClinVar as [Benign]. Clinvar id is 475320.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 = 0.0169 (2570/152052) while in subpopulation NFE AF= 0.0285 (1934/67976). AF 95% confidence interval is 0.0274. There are 49 homozygotes in gnomad4. There are 1207 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.39_41delTCT	p.Leu14del	disruptive_inframe_deletion	Exon 1 of 3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.39_41delTCT	p.Leu14del	disruptive_inframe_deletion	Exon 2 of 4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.39_41delTCT	p.Leu14del	disruptive_inframe_deletion	Exon 1 of 3	1	NM_198271.5	ENSP00000414670.3
LMOD3	ENST00000475434.1	c.39_41delTCT	p.Leu14del	disruptive_inframe_deletion	Exon 2 of 4	5		ENSP00000418645.1
LMOD3	ENST00000489031.5	c.39_41delTCT	p.Leu14del	disruptive_inframe_deletion	Exon 2 of 4	2		ENSP00000417210.1

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2571 AN: 151934 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00488

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0100

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0186 AC: 4579 AN: 246090 Hom.: 64 AF XY: 0.0194 AC XY: 2595 AN XY: 133450

Gnomad AFR exome AF: 0.00505

Gnomad AMR exome AF: 0.00892

Gnomad ASJ exome AF: 0.00793

Gnomad EAS exome AF: 0.00141

Gnomad SAS exome AF: 0.0225

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.0272

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0260 AC: 37904 AN: 1458732 Hom.: 566 AF XY: 0.0260 AC XY: 18868 AN XY: 725650

Gnomad4 AFR exome AF: 0.00427

Gnomad4 AMR exome AF: 0.00915

Gnomad4 ASJ exome AF: 0.00744

Gnomad4 EAS exome AF: 0.00154

Gnomad4 SAS exome AF: 0.0236

Gnomad4 FIN exome AF: 0.0142

Gnomad4 NFE exome AF: 0.0296

Gnomad4 OTH exome AF: 0.0227

GnomAD4 genome AF: 0.0169 AC: 2570 AN: 152052 Hom.: 49 Cov.: 32 AF XY: 0.0162 AC XY: 1207 AN XY: 74316

Gnomad4 AFR AF: 0.00487

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.0185

Gnomad4 FIN AF: 0.0100

Gnomad4 NFE AF: 0.0285

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.0209 Hom.: 14

Bravo AF: 0.0164

Asia WGS AF: 0.00924 AC: 33 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 10 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs139192915; hg19: chr3-69171496;