rs6810145

chr3-69119042-T-A

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.1313A>T(p.Lys438Met) variant causes a missense change. The variant allele was found at a frequency of 0.000941 in 1,613,758 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K438E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0048 (7 hom., cov: 31)
  • Exomes 𝑓: 0.00054 (6 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.63

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=0.0029786527).
• BP6: Variant 3-69119042-T-A is Benign according to our data. Variant chr3-69119042-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 475302.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 = 0.0048 (730/152080) while in subpopulation AFR AF= 0.0167 (692/41452). AF 95% confidence interval is 0.0157. There are 7 homozygotes in gnomad4. There are 344 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMOD3	NM_198271.5	c.1313A>T	p.Lys438Met	missense_variant	2/3	ENST00000420581.7
LMOD3	NM_001304418.3	c.1313A>T	p.Lys438Met	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMOD3	ENST00000420581.7	c.1313A>T	p.Lys438Met	missense_variant	2/3	1	NM_198271.5	P1
LMOD3	ENST00000475434.1	c.1313A>T	p.Lys438Met	missense_variant	3/4	5		P1
LMOD3	ENST00000489031.5	c.1313A>T	p.Lys438Met	missense_variant	3/4	2		P1

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 728 AN: 151962 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00120 AC: 298 AN: 249024 Hom.: 0 AF XY: 0.000977 AC XY: 132 AN XY: 135084

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.000927

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000540 AC: 789 AN: 1461678 Hom.: 6 Cov.: 33 AF XY: 0.000499 AC XY: 363 AN XY: 727118

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00480 AC: 730 AN: 152080 Hom.: 7 Cov.: 31 AF XY: 0.00463 AC XY: 344 AN XY: 74360

Gnomad4 AFR AF: 0.0167

Gnomad4 AMR AF: 0.00170

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: 0.00380

Alfa AF: 0.000925 Hom.: 0

Bravo AF: 0.00564

ESP6500AA AF: 0.0171 AC: 67

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00139 AC: 168

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely 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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	19
Dann	Benign	0.33
DEOGEN2	Benign	0.0031	T;T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.45	N
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.0	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.82	N;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.18
MVP		0.26
MPC		0.022
ClinPred		0.014	T
GERP RS		5.8
Varity_R		0.055
gMVP		0.18

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: rs6810145; hg19: chr3-69168193;