rs111797345

chr3-69119477-C-T

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: 7.91

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 -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 id is 475334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69119477-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMOD3	NM_198271.5	c.878G>A	p.Gly293Asp	missense_variant	2/3	ENST00000420581.7
LMOD3	NM_001304418.3	c.878G>A	p.Gly293Asp	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMOD3	ENST00000420581.7	c.878G>A	p.Gly293Asp	missense_variant	2/3	1	NM_198271.5	P1
LMOD3	ENST00000475434.1	c.878G>A	p.Gly293Asp	missense_variant	3/4	5		P1
LMOD3	ENST00000489031.5	c.878G>A	p.Gly293Asp	missense_variant	3/4	2		P1

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

GnomAD3 exomes AF: 0.0169 AC: 4201 AN: 248974 Hom.: 76 AF XY: 0.0176 AC XY: 2373 AN XY: 135048

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 SAS exome AF: 0.0142

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

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.00892

Gnomad4 ASJ exome AF: 0.00792

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.0563

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.0194

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

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.0636

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0155 Hom.: 34

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

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 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

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;T;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.2	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.028	D;D;D
Sift4G	Benign	0.43	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.36
MPC		0.18
ClinPred		0.027	T
GERP RS		5.7
Varity_R		0.32
gMVP		0.70

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: rs111797345; hg19: chr3-69168628;