3-69108943-T-G

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.*152A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 637,716 control chromosomes in the GnomAD database, including 1,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (305 hom., cov: 31)
  • Exomes 𝑓: 0.038 (1604 hom.)
• Consequence: LMOD3 NM_198271.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.235

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=-0.64).
• BP6: Variant 3-69108943-T-G is Benign according to our data. Variant chr3-69108943-T-G is described in ClinVar as [Benign]. Clinvar id is 1222613.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMOD3	NM_198271.5	c.*152A>C		3_prime_UTR_variant	3/3	ENST00000420581.7
LMOD3	NM_001304418.3	c.*152A>C		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMOD3	ENST00000420581.7	c.*152A>C		3_prime_UTR_variant	3/3	1	NM_198271.5	P1
LMOD3	ENST00000475434.1	c.*152A>C		3_prime_UTR_variant	4/4	5		P1
LMOD3	ENST00000489031.5	c.*152A>C		3_prime_UTR_variant	4/4	2		P1

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5435 AN: 152160 Hom.: 302 Cov.: 31

Gnomad AFR AF: 0.0550

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0311

GnomAD4 exome AF: 0.0378 AC: 18341 AN: 485436 Hom.: 1604 Cov.: 7 AF XY: 0.0414 AC XY: 10563 AN XY: 254956

Gnomad4 AFR exome AF: 0.0565

Gnomad4 AMR exome AF: 0.0182

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.275

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.00473

Gnomad4 NFE exome AF: 0.00930

Gnomad4 OTH exome AF: 0.0310

GnomAD4 genome AF: 0.0358 AC: 5448 AN: 152280 Hom.: 305 Cov.: 31 AF XY: 0.0395 AC XY: 2944 AN XY: 74452

Gnomad4 AFR AF: 0.0552

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.265

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.0183 Hom.: 19

Bravo AF: 0.0372

Asia WGS AF: 0.159 AC: 555 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

Aug 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	2.3
Dann	Benign	0.87

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: rs1131960; hg19: chr3-69158094; COSMIC: COSV56235583; COSMIC: COSV56235583;