rs116440123

Variant names:

• chr3-69118862-C-T
• rs116440123
• NM_198271.5:c.1493G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-69118862-C-T
• chr3-69118862-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198271.5(LMOD3):​c.1493G>A​(p.Arg498Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0009 in 1,610,134 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R498W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 30)
  • Exomes 𝑓: 0.00052 (10 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.33
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041202903).
• BP6: Variant 3-69118862-C-T is Benign according to our data. Variant chr3-69118862-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00465 (691/148564) while in subpopulation AFR AF = 0.0163 (656/40186). AF 95% confidence interval is 0.0153. There are 7 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

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.1493G>A	p.Arg498Gln	missense	Exon 2 of 3	NP_938012.2	Q0VAK6-1
	LMOD3	NM_001304418.3		c.1493G>A	p.Arg498Gln	missense	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.1493G>A	p.Arg498Gln	missense	Exon 2 of 3	ENSP00000414670.3	Q0VAK6-1
	LMOD3	ENST00000475434.1	TSL:5	c.1493G>A	p.Arg498Gln	missense	Exon 3 of 4	ENSP00000418645.1	Q0VAK6-1
	LMOD3	ENST00000489031.5	TSL:2	c.1493G>A	p.Arg498Gln	missense	Exon 3 of 4	ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 692 AN: 148446 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00299

GnomAD2 exomes AF: 0.00128 AC: 318 AN: 248434 AF XY: 0.000964

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.000986

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000889

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000519 AC: 758 AN: 1461570 Hom.: 10 Cov.: 33 AF XY: 0.000433 AC XY: 315 AN XY: 727072

African (AFR) AF: 0.0165 AC: 554 AN: 33478

American (AMR) AF: 0.000962 AC: 43 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39664

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.0000666 AC: 74 AN: 1111818

Other (OTH) AF: 0.00124 AC: 75 AN: 60364

GnomAD4 genome AF: 0.00465 AC: 691 AN: 148564 Hom.: 7 Cov.: 30 AF XY: 0.00437 AC XY: 315 AN XY: 72112

African (AFR) AF: 0.0163 AC: 656 AN: 40186

American (AMR) AF: 0.00136 AC: 20 AN: 14712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.000227 AC: 1 AN: 4404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10238

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67232

Other (OTH) AF: 0.00296 AC: 6 AN: 2028

Alfa AF: 0.00182 Hom.: 3

Bravo AF: 0.00548

ESP6500AA AF: 0.0157 AC: 63

ESP6500EA AF: 0.000359 AC: 3

ExAC AF: 0.00145 AC: 176

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Nemaline myopathy 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Benign	0.067
Eigen_PC	Benign	0.090
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.058
Sift	Benign	0.047	D
Sift4G	Benign	0.14	T
Polyphen		0.96	D
Vest4		0.18
MVP		0.25
MPC		0.068
ClinPred		0.020	T
GERP RS		5.0
Varity_R		0.059
gMVP		0.21
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs116440123; hg19: chr3-69168013; COSMIC: COSV70455778;