rs78574883

chr3-69122135-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.252G>A(p.Met84Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0016 in 1,612,738 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (14 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.17

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=0.0067123175).
• BP6: Variant 3-69122135-C-T is Benign according to our data. Variant chr3-69122135-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 435783.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 = 0.00889 (1354/152256) while in subpopulation AFR AF= 0.0307 (1275/41552). AF 95% confidence interval is 0.0293. There are 17 homozygotes in gnomad4. There are 644 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.252G>A	p.Met84Ile	missense_variant	1/3	ENST00000420581.7
LMOD3	NM_001304418.3	c.252G>A	p.Met84Ile	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMOD3	ENST00000420581.7	c.252G>A	p.Met84Ile	missense_variant	1/3	1	NM_198271.5	P1
LMOD3	ENST00000475434.1	c.252G>A	p.Met84Ile	missense_variant	2/4	5		P1
LMOD3	ENST00000489031.5	c.252G>A	p.Met84Ile	missense_variant	2/4	2		P1

Frequencies

GnomAD3 genomes AF: 0.00885 AC: 1346 AN: 152138 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

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: 0.0000882

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00228 AC: 563 AN: 246844 Hom.: 7 AF XY: 0.00171 AC XY: 229 AN XY: 133834

Gnomad AFR exome AF: 0.0339

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.000837 AC: 1222 AN: 1460482 Hom.: 14 Cov.: 31 AF XY: 0.000724 AC XY: 526 AN XY: 726362

Gnomad4 AFR exome AF: 0.0305

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00889 AC: 1354 AN: 152256 Hom.: 17 Cov.: 32 AF XY: 0.00865 AC XY: 644 AN XY: 74452

Gnomad4 AFR AF: 0.0307

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00168 Hom.: 7

Bravo AF: 0.00968

ESP6500AA AF: 0.0302 AC: 114

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00278 AC: 336

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 24, 2015

- -

Nemaline myopathy 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0034	T;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.88	D
MetaRNN	Benign	0.0067	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.098
Sift	Uncertain	0.027	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.70	P;P;P
Vest4		0.37
MutPred		0.44		Gain of glycosylation at S81 (P = 0.0162);Gain of glycosylation at S81 (P = 0.0162);Gain of glycosylation at S81 (P = 0.0162);
MVP		0.24
MPC		0.041
ClinPred		0.036	T
GERP RS		5.7
Varity_R		0.59
gMVP		0.19

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: rs78574883; hg19: chr3-69171286;