NM_198271.5:c.296A>G

Variant names:

• chr3-69120059-T-C
• rs1258289949
• NM_198271.5:c.296A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198271.5(LMOD3):​c.296A>G​(p.Glu99Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000314 in 1,593,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LMOD3 NM_198271.5 missense, splice_region
• Scores: Splicing: ADA: 0.0008430
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10
• Publications: 1 publications found

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]

LMOD3 Gene-Disease associations (from GenCC):

• nemaline myopathy 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06961623).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	NM_198271.5	MANE Select	c.296A>G	p.Glu99Gly	missense splice_region	Exon 2 of 3	NP_938012.2	Q0VAK6-1
	LMOD3	NM_001304418.3		c.296A>G	p.Glu99Gly	missense splice_region	Exon 3 of 4	NP_001291347.1	Q0VAK6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	ENST00000420581.7	TSL:1 MANE Select	c.296A>G	p.Glu99Gly	missense splice_region	Exon 2 of 3	ENSP00000414670.3	Q0VAK6-1
	LMOD3	ENST00000475434.1	TSL:5	c.296A>G	p.Glu99Gly	missense splice_region	Exon 3 of 4	ENSP00000418645.1	Q0VAK6-1
	LMOD3	ENST00000489031.5	TSL:2	c.296A>G	p.Glu99Gly	missense splice_region	Exon 3 of 4	ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00000871 AC: 2 AN: 229492 AF XY: 0.0000160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000643

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1441544 Hom.: 0 Cov.: 31 AF XY: 0.00000419 AC XY: 3 AN XY: 716676

African (AFR) AF: 0.00 AC: 0 AN: 32066

American (AMR) AF: 0.0000488 AC: 2 AN: 41004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25436

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 81924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5188

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106618

Other (OTH) AF: 0.0000168 AC: 1 AN: 59498

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000314 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Nemaline myopathy 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.010
Sift	Uncertain	0.019	D
Sift4G	Benign	0.11	T
Polyphen		0.0040	B
Vest4		0.091
MutPred		0.40		Loss of helix (P = 0.0041)
MVP		0.42
MPC		0.021
ClinPred		0.16	T
GERP RS		3.0
Varity_R		0.10
gMVP		0.062
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00084
dbscSNV1_RF	Benign	0.046
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

Other links and lift over

dbSNP: rs1258289949; hg19: chr3-69169210;