rs115972674

Positions:

• chr3-69119596-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198271.5(LMOD3):​c.759T>C​(p.Pro253Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,613,726 control chromosomes in the GnomAD database, including 1,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (92 hom., cov: 31)
  • Exomes 𝑓: 0.040 (1385 hom.)
• Consequence: LMOD3 NM_198271.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.334

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-69119596-A-G is Benign according to our data. Variant chr3-69119596-A-G is described in ClinVar as [Benign]. Clinvar id is 475332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.334 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0291 (4436/152274) while in subpopulation NFE AF= 0.0473 (3214/68016). AF 95% confidence interval is 0.0459. There are 92 homozygotes in gnomad4. There are 2071 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 92 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.759T>C	p.Pro253Pro	synonymous_variant	2/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.759T>C	p.Pro253Pro	synonymous_variant	3/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.759T>C	p.Pro253Pro	synonymous_variant	2/3	1	NM_198271.5	ENSP00000414670.3
LMOD3	ENST00000475434.1	c.759T>C	p.Pro253Pro	synonymous_variant	3/4	5		ENSP00000418645.1
LMOD3	ENST00000489031.5	c.759T>C	p.Pro253Pro	synonymous_variant	3/4	2		ENSP00000417210.1

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4438 AN: 152156 Hom.: 92 Cov.: 31

Gnomad AFR AF: 0.00688

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0473

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0307 AC: 7646 AN: 248964 Hom.: 177 AF XY: 0.0315 AC XY: 4249 AN XY: 135078

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.0355

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0142

Gnomad FIN exome AF: 0.0232

Gnomad NFE exome AF: 0.0481

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0404 AC: 59067 AN: 1461452 Hom.: 1385 Cov.: 33 AF XY: 0.0400 AC XY: 29052 AN XY: 727004

Gnomad4 AFR exome AF: 0.00705

Gnomad4 AMR exome AF: 0.0200

Gnomad4 ASJ exome AF: 0.0365

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.0213

Gnomad4 NFE exome AF: 0.0470

Gnomad4 OTH exome AF: 0.0349

GnomAD4 genome AF: 0.0291 AC: 4436 AN: 152274 Hom.: 92 Cov.: 31 AF XY: 0.0278 AC XY: 2071 AN XY: 74470

Gnomad4 AFR AF: 0.00686

Gnomad4 AMR AF: 0.0261

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.0473

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0402 Hom.: 54

Bravo AF: 0.0296

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0488

EpiControl AF: 0.0525

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2019	- -

Nemaline myopathy 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.1
DANN	Benign	0.62

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: rs115972674; hg19: chr3-69168747; COSMIC: COSV70455658;