3-69122240-G-A

Position:

• chr3-69122240-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Strong BP6_Moderate BP7 BS1

The NM_198271.5(LMOD3):​c.147C>T​(p.Pro49=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,613,494 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: LMOD3 NM_198271.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -4.01

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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 3-69122240-G-A is Benign according to our data. Variant chr3-69122240-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 542092.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000217 (33/152146) while in subpopulation AMR AF= 0.00164 (25/15286). AF 95% confidence interval is 0.00114. There are 1 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.147C>T	p.Pro49=	synonymous_variant	1/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.147C>T	p.Pro49=	synonymous_variant	2/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.147C>T	p.Pro49=	synonymous_variant	1/3	1	NM_198271.5	ENSP00000414670	P1
LMOD3	ENST00000475434.1	c.147C>T	p.Pro49=	synonymous_variant	2/4	5		ENSP00000418645	P1
LMOD3	ENST00000489031.5	c.147C>T	p.Pro49=	synonymous_variant	2/4	2		ENSP00000417210	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152028 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.0000403 AC: 10 AN: 248278 Hom.: 0 AF XY: 0.0000594 AC XY: 8 AN XY: 134706

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1461348 Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27 AN XY: 726924

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152146 Hom.: 1 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74382

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000900 Hom.: 0

Bravo AF: 0.000450

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2023

- -

LMOD3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.8
DANN	Benign	0.79

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: rs184423475; hg19: chr3-69171391;