3-69109250-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_198271.5(LMOD3):c.1657-129A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 772,552 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0092 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0062 (32 hom.)
• Consequence: LMOD3 NM_198271.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.273

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-69109250-T-C is Benign according to our data. Variant chr3-69109250-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1190601.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00923 (1405/152230) while in subpopulation AFR AF= 0.0151 (627/41540). AF 95% confidence interval is 0.0141. There are 12 homozygotes in gnomad4. There are 642 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMOD3	NM_198271.5	c.1657-129A>G		intron_variant		ENST00000420581.7
LMOD3	NM_001304418.3	c.1657-129A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMOD3	ENST00000420581.7	c.1657-129A>G		intron_variant		1	NM_198271.5	P1
LMOD3	ENST00000475434.1	c.1657-129A>G		intron_variant		5		P1
LMOD3	ENST00000489031.5	c.1657-129A>G		intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.00921 AC: 1401 AN: 152112 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00670

Gnomad OTH AF: 0.0210

GnomAD4 exome AF: 0.00619 AC: 3837 AN: 620322 Hom.: 32 AF XY: 0.00618 AC XY: 2026 AN XY: 327780

Gnomad4 AFR exome AF: 0.0164

Gnomad4 AMR exome AF: 0.00896

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00529

Gnomad4 FIN exome AF: 0.000507

Gnomad4 NFE exome AF: 0.00583

Gnomad4 OTH exome AF: 0.00958

GnomAD4 genome AF: 0.00923 AC: 1405 AN: 152230 Hom.: 12 Cov.: 31 AF XY: 0.00863 AC XY: 642 AN XY: 74434

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00671

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.00826 Hom.: 1

Bravo AF: 0.0107

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	2.2
Dann	Benign	0.74

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: rs114228075; hg19: chr3-69158401;