rs199592188

Variant names:

• chr3-69119165-T-C
• rs199592188
• NM_198271.5:c.1190A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-69119165-T-C
• chr3-69119165-T-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198271.5(LMOD3):​c.1190A>G​(p.Gln397Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00211 in 1,613,880 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q397E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (6 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 6.26
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013280481).
• BP6: Variant 3-69119165-T-C is Benign according to our data. Variant chr3-69119165-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475293.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00151 (230/152204) while in subpopulation NFE AF = 0.00257 (175/68002). AF 95% confidence interval is 0.00226. There are 1 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1190A>G	p.Gln397Arg	missense	Exon 2 of 3	NP_938012.2	Q0VAK6-1
	LMOD3	NM_001304418.3		c.1190A>G	p.Gln397Arg	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.1190A>G	p.Gln397Arg	missense	Exon 2 of 3	ENSP00000414670.3	Q0VAK6-1
	LMOD3	ENST00000475434.1	TSL:5	c.1190A>G	p.Gln397Arg	missense	Exon 3 of 4	ENSP00000418645.1	Q0VAK6-1
	LMOD3	ENST00000489031.5	TSL:2	c.1190A>G	p.Gln397Arg	missense	Exon 3 of 4	ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 152086 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.00169 AC: 421 AN: 249000 AF XY: 0.00173

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00223

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00218 AC: 3180 AN: 1461676 Hom.: 6 Cov.: 33 AF XY: 0.00214 AC XY: 1553 AN XY: 727118

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00230 AC: 123 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00264 AC: 2934 AN: 1111840

Other (OTH) AF: 0.00161 AC: 97 AN: 60374

GnomAD4 genome AF: 0.00151 AC: 230 AN: 152204 Hom.: 1 Cov.: 31 AF XY: 0.00160 AC XY: 119 AN XY: 74430

African (AFR) AF: 0.000578 AC: 24 AN: 41522

American (AMR) AF: 0.00105 AC: 16 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00257 AC: 175 AN: 68002

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00202 Hom.: 0

Bravo AF: 0.00163

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000776 AC: 3

ESP6500EA AF: 0.00265 AC: 22

ExAC AF: 0.00187 AC: 226

EpiCase AF: 0.00213

EpiControl AF: 0.00231

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	LMOD3-related disorder (1)
-	-	1	Nemaline myopathy 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.079	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.3
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.31
Sift	Benign	0.21	T
Sift4G	Uncertain	0.059	T
Polyphen		0.027	B
Vest4		0.25
MVP		0.88
MPC		0.022
ClinPred		0.043	T
GERP RS		4.3
Varity_R		0.28
gMVP		0.47
Mutation Taster		=97/3	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: rs199592188; hg19: chr3-69168316; COSMIC: COSV106115013;