3-69109147-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198271.5(LMOD3):c.1657-26C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00755 in 1,593,666 control chromosomes in the GnomAD database, including 485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (202 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (283 hom.)
• Consequence: LMOD3 NM_198271.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.171

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=-0.81).
• BP6: Variant 3-69109147-G-C is Benign according to our data. Variant chr3-69109147-G-C is described in ClinVar as [Benign]. Clinvar id is 1242359.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMOD3	NM_198271.5	c.1657-26C>G		intron_variant		ENST00000420581.7
LMOD3	NM_001304418.3	c.1657-26C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMOD3	ENST00000420581.7	c.1657-26C>G		intron_variant		1	NM_198271.5	P1
LMOD3	ENST00000475434.1	c.1657-26C>G		intron_variant		5		P1
LMOD3	ENST00000489031.5	c.1657-26C>G		intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4583 AN: 152092 Hom.: 201 Cov.: 32

Gnomad AFR AF: 0.0962

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0543

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0110 AC: 2333 AN: 212876 Hom.: 71 AF XY: 0.00954 AC XY: 1094 AN XY: 114728

Gnomad AFR exome AF: 0.0970

Gnomad AMR exome AF: 0.00590

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0406

Gnomad SAS exome AF: 0.00598

Gnomad FIN exome AF: 0.0000536

Gnomad NFE exome AF: 0.000516

Gnomad OTH exome AF: 0.00608

GnomAD4 exome AF: 0.00515 AC: 7426 AN: 1441456 Hom.: 283 Cov.: 29 AF XY: 0.00484 AC XY: 3464 AN XY: 715164

Gnomad4 AFR exome AF: 0.0977

Gnomad4 AMR exome AF: 0.00682

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0621

Gnomad4 SAS exome AF: 0.00617

Gnomad4 FIN exome AF: 0.000291

Gnomad4 NFE exome AF: 0.000261

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0302 AC: 4604 AN: 152210 Hom.: 202 Cov.: 32 AF XY: 0.0297 AC XY: 2210 AN XY: 74428

Gnomad4 AFR AF: 0.0964

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0546

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.00220 Hom.: 3

Bravo AF: 0.0349

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.6
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs72924866; hg19: chr3-69158298; COSMIC: COSV56235045; COSMIC: COSV56235045;