rs200045981

Variant names:

• chr3-69118710-A-G
• rs200045981
• NM_198271.5:c.1645T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BS1_Supporting

The NM_198271.5(LMOD3):​c.1645T>C​(p.Tyr549His) variant causes a missense change. The variant allele was found at a frequency of 0.000574 in 1,611,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.05
• Publications: 4 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_198271.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.22268426).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000455 (69/151696) while in subpopulation NFE AF = 0.000692 (47/67928). AF 95% confidence interval is 0.000534. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	NM_198271.5	MANE Select	c.1645T>C	p.Tyr549His	missense	Exon 2 of 3	NP_938012.2
	LMOD3	NM_001304418.3		c.1645T>C	p.Tyr549His	missense	Exon 3 of 4	NP_001291347.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	ENST00000420581.7	TSL:1 MANE Select	c.1645T>C	p.Tyr549His	missense	Exon 2 of 3	ENSP00000414670.3
	LMOD3	ENST00000475434.1	TSL:5	c.1645T>C	p.Tyr549His	missense	Exon 3 of 4	ENSP00000418645.1
	LMOD3	ENST00000489031.5	TSL:2	c.1645T>C	p.Tyr549His	missense	Exon 3 of 4	ENSP00000417210.1

Frequencies

GnomAD3 genomes AF: 0.000449 AC: 68 AN: 151578 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000364

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000197

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: 0.000692

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.000497 AC: 123 AN: 247264 AF XY: 0.000529

Gnomad AFR exome AF: 0.000845

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000812

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000587 AC: 857 AN: 1460254 Hom.: 0 Cov.: 33 AF XY: 0.000555 AC XY: 403 AN XY: 726350

African (AFR) AF: 0.000509 AC: 17 AN: 33420

American (AMR) AF: 0.000158 AC: 7 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86116

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53374

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5750

European-Non Finnish (NFE) AF: 0.000704 AC: 782 AN: 1111214

Other (OTH) AF: 0.000448 AC: 27 AN: 60298

GnomAD4 genome AF: 0.000455 AC: 69 AN: 151696 Hom.: 0 Cov.: 30 AF XY: 0.000445 AC XY: 33 AN XY: 74090

African (AFR) AF: 0.000387 AC: 16 AN: 41328

American (AMR) AF: 0.000197 AC: 3 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000692 AC: 47 AN: 67928

Other (OTH) AF: 0.000952 AC: 2 AN: 2100

Alfa AF: 0.000662 Hom.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000766 AC: 3

ESP6500EA AF: 0.000722 AC: 6

ExAC AF: 0.000529 AC: 64

EpiCase AF: 0.00153

EpiControl AF: 0.00125

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.73
MVP		0.34
MPC		0.18
ClinPred		0.040	T
GERP RS		5.8
Varity_R		0.37
gMVP		0.38
Mutation Taster		=73/27	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: rs200045981; hg19: chr3-69167861; COSMIC: COSV70455893;