rs145387235

Variant names:

• chr3-69118700-G-T
• rs145387235
• NM_198271.5:c.1655C>A
• LMOD3 p.Pro552His

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_198271.5(LMOD3):​c.1655C>A​(p.Pro552His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,610,364 control chromosomes in the GnomAD database, including 285 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 30)
  • Exomes 𝑓: 0.017 (262 hom.)
• Consequence: LMOD3 NM_198271.5 missense, splice_region
• Scores: Splicing: ADA: 0.9584
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 9.47
• Publications: 9 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 3-69118700-G-T is Benign according to our data. Variant chr3-69118700-G-T is described in ClinVar as Benign. ClinVar VariationId is 475310.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 = 0.013 (1968/151808) while in subpopulation NFE AF = 0.0192 (1304/67942). AF 95% confidence interval is 0.0183. There are 23 homozygotes in GnomAd4. There are 922 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.1655C>A	p.Pro552His	missense splice_region	Exon 2 of 3	NP_938012.2	Q0VAK6-1
	LMOD3	NM_001304418.3		c.1655C>A	p.Pro552His	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.1655C>A	p.Pro552His	missense splice_region	Exon 2 of 3	ENSP00000414670.3	Q0VAK6-1
	LMOD3	ENST00000475434.1	TSL:5	c.1655C>A	p.Pro552His	missense splice_region	Exon 3 of 4	ENSP00000418645.1	Q0VAK6-1
	LMOD3	ENST00000489031.5	TSL:2	c.1655C>A	p.Pro552His	missense splice_region	Exon 3 of 4	ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1969 AN: 151690 Hom.: 23 Cov.: 30

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.00837

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0188

GnomAD2 exomes AF: 0.0124 AC: 3057 AN: 246034 AF XY: 0.0123

Gnomad AFR exome AF: 0.00385

Gnomad AMR exome AF: 0.0130

Gnomad ASJ exome AF: 0.00801

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0174 AC: 25410 AN: 1458556 Hom.: 262 Cov.: 33 AF XY: 0.0169 AC XY: 12247 AN XY: 725406

African (AFR) AF: 0.00330 AC: 110 AN: 33320

American (AMR) AF: 0.0141 AC: 624 AN: 44110

Ashkenazi Jewish (ASJ) AF: 0.00767 AC: 199 AN: 25946

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39592

South Asian (SAS) AF: 0.00178 AC: 153 AN: 86002

European-Finnish (FIN) AF: 0.0157 AC: 837 AN: 53332

Middle Eastern (MID) AF: 0.0117 AC: 67 AN: 5732

European-Non Finnish (NFE) AF: 0.0202 AC: 22455 AN: 1110304

Other (OTH) AF: 0.0160 AC: 964 AN: 60218

GnomAD4 genome AF: 0.0130 AC: 1968 AN: 151808 Hom.: 23 Cov.: 30 AF XY: 0.0124 AC XY: 922 AN XY: 74154

African (AFR) AF: 0.00435 AC: 180 AN: 41376

American (AMR) AF: 0.0162 AC: 247 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00837 AC: 29 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4778

European-Finnish (FIN) AF: 0.0148 AC: 156 AN: 10548

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0192 AC: 1304 AN: 67942

Other (OTH) AF: 0.0186 AC: 39 AN: 2100

Alfa AF: 0.0169 Hom.: 93

Bravo AF: 0.0131

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Nemaline myopathy 10 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.11	T
Varity_R		0.37
gMVP		0.18
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.74
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs145387235;

hg19: chr3-69167851;

COSMIC: COSV106115012;