rs111797345

Variant names:

• chr3-69119477-C-T
• rs111797345
• NM_198271.5:c.878G>A

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.878G>A​(p.Gly293Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,613,904 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (36 hom., cov: 31)
  • Exomes 𝑓: 0.019 (367 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.91
• Publications: 7 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=0.010550827).
• BP6: Variant 3-69119477-C-T is Benign according to our data. Variant chr3-69119477-C-T is described in ClinVar as Benign. ClinVar VariationId is 475334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0151 (2293/152242) while in subpopulation NFE AF = 0.0179 (1218/68008). AF 95% confidence interval is 0.0171. There are 36 homozygotes in GnomAd4. There are 1248 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 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.878G>A	p.Gly293Asp	missense	Exon 2 of 3	NP_938012.2	Q0VAK6-1
	LMOD3	NM_001304418.3		c.878G>A	p.Gly293Asp	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.878G>A	p.Gly293Asp	missense	Exon 2 of 3	ENSP00000414670.3	Q0VAK6-1
	LMOD3	ENST00000475434.1	TSL:5	c.878G>A	p.Gly293Asp	missense	Exon 3 of 4	ENSP00000418645.1	Q0VAK6-1
	LMOD3	ENST00000489031.5	TSL:2	c.878G>A	p.Gly293Asp	missense	Exon 3 of 4	ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2295 AN: 152124 Hom.: 36 Cov.: 31

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0636

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0169 AC: 4201 AN: 248974 AF XY: 0.0176

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00863

Gnomad ASJ exome AF: 0.00925

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0625

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0189 AC: 27582 AN: 1461662 Hom.: 367 Cov.: 33 AF XY: 0.0188 AC XY: 13670 AN XY: 727102

African (AFR) AF: 0.00242 AC: 81 AN: 33480

American (AMR) AF: 0.00892 AC: 399 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00792 AC: 207 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0151 AC: 1306 AN: 86258

European-Finnish (FIN) AF: 0.0563 AC: 3005 AN: 53384

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5768

European-Non Finnish (NFE) AF: 0.0192 AC: 21354 AN: 1111842

Other (OTH) AF: 0.0194 AC: 1169 AN: 60374

GnomAD4 genome AF: 0.0151 AC: 2293 AN: 152242 Hom.: 36 Cov.: 31 AF XY: 0.0168 AC XY: 1248 AN XY: 74434

African (AFR) AF: 0.00315 AC: 131 AN: 41554

American (AMR) AF: 0.0103 AC: 157 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4822

European-Finnish (FIN) AF: 0.0636 AC: 674 AN: 10598

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0179 AC: 1218 AN: 68008

Other (OTH) AF: 0.0128 AC: 27 AN: 2110

Alfa AF: 0.0152 Hom.: 65

Bravo AF: 0.0108

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0223 AC: 86

ESP6500AA AF: 0.00323 AC: 13

ESP6500EA AF: 0.0189 AC: 158

ExAC AF: 0.0154 AC: 1867

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0169

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.028	D
Sift4G	Benign	0.43	T
Polyphen		1.0	D
Vest4		0.36
MPC		0.18
ClinPred		0.027	T
GERP RS		5.7
Varity_R		0.32
gMVP		0.70
Mutation Taster		=95/5	polymorphism (auto)

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: rs111797345; hg19: chr3-69168628;