chr3-69109116-T-G

Variant names:

• chr3-69109116-T-G
• rs775236296
• NM_198271.5:c.1662A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198271.5(LMOD3):​c.1662A>C​(p.Gln554His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q554R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.349
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14263177).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	NM_198271.5	MANE Select	c.1662A>C	p.Gln554His	missense	Exon 3 of 3	NP_938012.2	Q0VAK6-1
	LMOD3	NM_001304418.3		c.1662A>C	p.Gln554His	missense	Exon 4 of 4	NP_001291347.1	Q0VAK6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMOD3	ENST00000420581.7	TSL:1 MANE Select	c.1662A>C	p.Gln554His	missense	Exon 3 of 3	ENSP00000414670.3	Q0VAK6-1
	LMOD3	ENST00000475434.1	TSL:5	c.1662A>C	p.Gln554His	missense	Exon 4 of 4	ENSP00000418645.1	Q0VAK6-1
	LMOD3	ENST00000489031.5	TSL:2	c.1662A>C	p.Gln554His	missense	Exon 4 of 4	ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450564 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 720240

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 43272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25878

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 83848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52582

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

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106440

Other (OTH) AF: 0.00 AC: 0 AN: 60010

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.35
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.092
Sift	Benign	0.033	D
Sift4G	Uncertain	0.047	D
Polyphen		0.64	P
Vest4		0.25
MutPred		0.27		Gain of glycosylation at Y549 (P = 0.0129)
MVP		0.27
MPC		0.042
ClinPred		0.23	T
GERP RS		-3.4
Varity_R		0.12
gMVP		0.18
Mutation Taster		=96/4	polymorphism

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: rs775236296; hg19: chr3-69158267;