3-69119713-C-T

Position:

• chr3-69119713-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_198271.5(LMOD3):​c.642G>A​(p.Ser214Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,613,790 control chromosomes in the GnomAD database, including 2,719 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (507 hom., cov: 31)
  • Exomes 𝑓: 0.019 (2212 hom.)
• Consequence: LMOD3 NM_198271.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.119

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-69119713-C-T is Benign according to our data. Variant chr3-69119713-C-T is described in ClinVar as [Benign]. Clinvar id is 475330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.119 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.642G>A	p.Ser214Ser	synonymous_variant	2/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.642G>A	p.Ser214Ser	synonymous_variant	3/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.642G>A	p.Ser214Ser	synonymous_variant	2/3	1	NM_198271.5	ENSP00000414670.3
LMOD3	ENST00000475434.1	c.642G>A	p.Ser214Ser	synonymous_variant	3/4	5		ENSP00000418645.1
LMOD3	ENST00000489031.5	c.642G>A	p.Ser214Ser	synonymous_variant	3/4	2		ENSP00000417210.1

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7258 AN: 152014 Hom.: 500 Cov.: 31

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.0326

GnomAD3 exomes AF: 0.0447 AC: 11144 AN: 249044 Hom.: 959 AF XY: 0.0457 AC XY: 6174 AN XY: 135108

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.244

Gnomad SAS exome AF: 0.126

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0188 AC: 27503 AN: 1461658 Hom.: 2212 Cov.: 33 AF XY: 0.0214 AC XY: 15568 AN XY: 727102

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.0190

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.229

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.00272

Gnomad4 NFE exome AF: 0.000646

Gnomad4 OTH exome AF: 0.0280

GnomAD4 genome AF: 0.0478 AC: 7275 AN: 152132 Hom.: 507 Cov.: 31 AF XY: 0.0505 AC XY: 3755 AN XY: 74376

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0166

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.225

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0116 Hom.: 56

Bravo AF: 0.0522

Asia WGS AF: 0.137 AC: 475 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nemaline myopathy 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.5
DANN	Benign	0.60

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: rs9815992; hg19: chr3-69168864; COSMIC: COSV70455836;