3-69119536-G-A

Variant names:

• chr3-69119536-G-A
• rs375767322
• NM_198271.5:c.819C>T

Variant summary

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

The ENST00000420581.7(LMOD3):​c.819C>T​(p.Asp273Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: LMOD3 ENST00000420581.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.94
• 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=-0.5).
• BP6: Variant 3-69119536-G-A is Benign according to our data. Variant chr3-69119536-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 542087.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.94 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000420581.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	NM_198271.5	MANE Select	c.819C>T	p.Asp273Asp	synonymous	Exon 2 of 3	NP_938012.2
	LMOD3	NM_001304418.3		c.819C>T	p.Asp273Asp	synonymous	Exon 3 of 4	NP_001291347.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	ENST00000420581.7	TSL:1 MANE Select	c.819C>T	p.Asp273Asp	synonymous	Exon 2 of 3	ENSP00000414670.3
	LMOD3	ENST00000475434.1	TSL:5	c.819C>T	p.Asp273Asp	synonymous	Exon 3 of 4	ENSP00000418645.1
	LMOD3	ENST00000489031.5	TSL:2	c.819C>T	p.Asp273Asp	synonymous	Exon 3 of 4	ENSP00000417210.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152192 Hom.: 0 Cov.: 31

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: 0.0000442 AC: 11 AN: 249002 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000798

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461630 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 727094

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111862

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152192 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74354

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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: 10614

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000302

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Nemaline myopathy 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.8
DANN	Benign	0.42
PhyloP100		1.9

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: rs375767322; hg19: chr3-69168687;