rs947092258

Variant names:

• chr3-69109119-C-A
• rs947092258
• NM_198271.5:c.1659G>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_198271.5(LMOD3):​c.1659G>T​(p.Val553Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000612 in 1,602,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: LMOD3 NM_198271.5 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.112
• Publications: 0 publications found

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]

LMOD3 Gene-Disease associations (from GenCC):

• nemaline myopathy 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 3-69109119-C-A is Benign according to our data. Variant chr3-69109119-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 475311.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.112 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.1659G>T	p.Val553Val	splice_region_variant, synonymous_variant	Exon 3 of 3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.1659G>T	p.Val553Val	splice_region_variant, synonymous_variant	Exon 4 of 4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.1659G>T	p.Val553Val	splice_region_variant, synonymous_variant	Exon 3 of 3	1	NM_198271.5	ENSP00000414670.3
LMOD3	ENST00000475434.1	c.1659G>T	p.Val553Val	splice_region_variant, synonymous_variant	Exon 4 of 4	5		ENSP00000418645.1
LMOD3	ENST00000489031.5	c.1659G>T	p.Val553Val	splice_region_variant, synonymous_variant	Exon 4 of 4	2		ENSP00000417210.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000132 AC: 3 AN: 227084 AF XY: 0.0000163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000198

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.0000648 AC: 94 AN: 1450136 Hom.: 0 Cov.: 29 AF XY: 0.0000694 AC XY: 50 AN XY: 719962

African (AFR) AF: 0.00 AC: 0 AN: 33346

American (AMR) AF: 0.0000231 AC: 1 AN: 43222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25868

East Asian (EAS) AF: 0.00 AC: 0 AN: 39392

South Asian (SAS) AF: 0.00 AC: 0 AN: 83806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000814 AC: 90 AN: 1106262

Other (OTH) AF: 0.0000500 AC: 3 AN: 59986

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 10 Benign:1

Apr 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.6
DANN	Benign	0.72
PhyloP100		-0.11

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

Other links and lift over

dbSNP: rs947092258; hg19: chr3-69158270;