NM_198271.5:c.*15A>G

Variant names:

• chr3-69109080-T-C
• rs60474520
• NM_198271.5:c.*15A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198271.5(LMOD3):​c.*15A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0274 in 1,593,222 control chromosomes in the GnomAD database, including 2,886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (305 hom., cov: 32)
  • Exomes 𝑓: 0.026 (2581 hom.)
• Consequence: LMOD3 NM_198271.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0830
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-69109080-T-C is Benign according to our data. Variant chr3-69109080-T-C is described in ClinVar as Benign. ClinVar VariationId is 1180899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

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.*15A>G		3_prime_UTR	Exon 3 of 3	NP_938012.2	Q0VAK6-1
	LMOD3	NM_001304418.3		c.*15A>G		3_prime_UTR	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.*15A>G		3_prime_UTR	Exon 3 of 3	ENSP00000414670.3	Q0VAK6-1
	LMOD3	ENST00000475434.1	TSL:5	c.*15A>G		3_prime_UTR	Exon 4 of 4	ENSP00000418645.1	Q0VAK6-1
	LMOD3	ENST00000489031.5	TSL:2	c.*15A>G		3_prime_UTR	Exon 4 of 4	ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5440 AN: 152196 Hom.: 302 Cov.: 32

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0498 AC: 10792 AN: 216830 AF XY: 0.0516

Gnomad AFR exome AF: 0.0541

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.282

Gnomad FIN exome AF: 0.00382

Gnomad NFE exome AF: 0.00912

Gnomad OTH exome AF: 0.0337

GnomAD4 exome AF: 0.0265 AC: 38140 AN: 1440908 Hom.: 2581 Cov.: 29 AF XY: 0.0292 AC XY: 20870 AN XY: 714956

African (AFR) AF: 0.0600 AC: 1991 AN: 33166

American (AMR) AF: 0.0231 AC: 970 AN: 41976

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 391 AN: 25746

East Asian (EAS) AF: 0.277 AC: 10827 AN: 39038

South Asian (SAS) AF: 0.130 AC: 10764 AN: 82680

European-Finnish (FIN) AF: 0.00487 AC: 254 AN: 52128

Middle Eastern (MID) AF: 0.0256 AC: 147 AN: 5738

European-Non Finnish (NFE) AF: 0.00980 AC: 10782 AN: 1100762

Other (OTH) AF: 0.0338 AC: 2014 AN: 59674

GnomAD4 genome AF: 0.0358 AC: 5453 AN: 152314 Hom.: 305 Cov.: 32 AF XY: 0.0395 AC XY: 2944 AN XY: 74484

African (AFR) AF: 0.0550 AC: 2286 AN: 41560

American (AMR) AF: 0.0160 AC: 244 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.265 AC: 1371 AN: 5178

South Asian (SAS) AF: 0.139 AC: 671 AN: 4830

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10628

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 726 AN: 68036

Other (OTH) AF: 0.0307 AC: 65 AN: 2114

Alfa AF: 0.0189 Hom.: 24

Bravo AF: 0.0373

Asia WGS AF: 0.159 AC: 555 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.43
PhyloP100		-0.083
Mutation Taster		=100/0	polymorphism (auto)

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: rs60474520; hg19: chr3-69158231; COSMIC: COSV56235588; COSMIC: COSV56235588;