rs74350755

chr3-69119211-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198271.5(LMOD3):c.1144C>T(p.Pro382Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,864 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (17 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (10 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.021602124).
• BP6: Variant 3-69119211-G-A is Benign according to our data. Variant chr3-69119211-G-A is described in ClinVar as [Benign]. Clinvar id is 475296.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 = 0.00753 (1146/152168) while in subpopulation AFR AF= 0.0247 (1026/41492). AF 95% confidence interval is 0.0235. There are 17 homozygotes in gnomad4. There are 522 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMOD3	NM_198271.5	c.1144C>T	p.Pro382Ser	missense_variant	2/3	ENST00000420581.7
LMOD3	NM_001304418.3	c.1144C>T	p.Pro382Ser	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMOD3	ENST00000420581.7	c.1144C>T	p.Pro382Ser	missense_variant	2/3	1	NM_198271.5	P1
LMOD3	ENST00000475434.1	c.1144C>T	p.Pro382Ser	missense_variant	3/4	5		P1
LMOD3	ENST00000489031.5	c.1144C>T	p.Pro382Ser	missense_variant	3/4	2		P1

Frequencies

GnomAD3 genomes AF: 0.00752 AC: 1143 AN: 152050 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

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: 0.0000588

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00182 AC: 454 AN: 248966 Hom.: 8 AF XY: 0.00131 AC XY: 177 AN XY: 135048

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000731 AC: 1069 AN: 1461696 Hom.: 10 Cov.: 33 AF XY: 0.000616 AC XY: 448 AN XY: 727128

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00753 AC: 1146 AN: 152168 Hom.: 17 Cov.: 31 AF XY: 0.00702 AC XY: 522 AN XY: 74394

Gnomad4 AFR AF: 0.0247

Gnomad4 AMR AF: 0.00648

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00125 Hom.: 6

Bravo AF: 0.00901

ESP6500AA AF: 0.0189 AC: 72

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00216 AC: 261

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;T;T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.97	D
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.85
MVP		0.99
MPC		0.17
ClinPred		0.048	T
GERP RS		5.8
Varity_R		0.67
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs74350755; hg19: chr3-69168362;