3-69109099-G-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.1679C>T(p.Ala560Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,600,788 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A560A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (29 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.314

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=0.0030201077).
• BP6: Variant 3-69109099-G-A is Benign according to our data. Variant chr3-69109099-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475312.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 = 0.0123 (1873/152162) while in subpopulation AFR AF= 0.0421 (1746/41494). AF 95% confidence interval is 0.0404. There are 46 homozygotes in gnomad4. There are 869 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMOD3	NM_198271.5	c.1679C>T	p.Ala560Val	missense_variant	3/3	ENST00000420581.7
LMOD3	NM_001304418.3	c.1679C>T	p.Ala560Val	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMOD3	ENST00000420581.7	c.1679C>T	p.Ala560Val	missense_variant	3/3	1	NM_198271.5	P1
LMOD3	ENST00000475434.1	c.1679C>T	p.Ala560Val	missense_variant	4/4	5		P1
LMOD3	ENST00000489031.5	c.1679C>T	p.Ala560Val	missense_variant	4/4	2		P1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1871 AN: 152044 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00518

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00316 AC: 714 AN: 225744 Hom.: 12 AF XY: 0.00235 AC XY: 287 AN XY: 121936

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.00216

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.0000599

Gnomad SAS exome AF: 0.0000362

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000710

GnomAD4 exome AF: 0.00136 AC: 1975 AN: 1448626 Hom.: 29 Cov.: 29 AF XY: 0.00122 AC XY: 880 AN XY: 719140

Gnomad4 AFR exome AF: 0.0441

Gnomad4 AMR exome AF: 0.00283

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000598

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00289

GnomAD4 genome AF: 0.0123 AC: 1873 AN: 152162 Hom.: 46 Cov.: 32 AF XY: 0.0117 AC XY: 869 AN XY: 74394

Gnomad4 AFR AF: 0.0421

Gnomad4 AMR AF: 0.00517

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00292 Hom.: 12

Bravo AF: 0.0144

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0438 AC: 166

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.00364 AC: 439

Asia WGS AF: 0.00173 AC: 7 AN: 3478

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 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	7.3
Dann	Benign	0.93
DEOGEN2	Benign	0.0034	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.72	P;P;P
Vest4		0.16
MVP		0.11
MPC		0.020
ClinPred		0.033	T
GERP RS		-4.3
Varity_R		0.16
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs17005363; hg19: chr3-69158250;