NM_198271.5:c.*152A>C

Variant names:

• chr3-69108943-T-G
• rs1131960
• NM_198271.5:c.*152A>C

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.*152A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 637,716 control chromosomes in the GnomAD database, including 1,909 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: 31)
  • Exomes 𝑓: 0.038 (1604 hom.)
• Consequence: LMOD3 NM_198271.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.235
• Publications: 4 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=-0.64).
• BP6: Variant 3-69108943-T-G is Benign according to our data. Variant chr3-69108943-T-G is described in ClinVar as Benign. ClinVar VariationId is 1222613.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.*152A>C		3_prime_UTR	Exon 3 of 3	NP_938012.2	Q0VAK6-1
	LMOD3	NM_001304418.3		c.*152A>C		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.*152A>C		3_prime_UTR	Exon 3 of 3	ENSP00000414670.3	Q0VAK6-1
	LMOD3	ENST00000475434.1	TSL:5	c.*152A>C		3_prime_UTR	Exon 4 of 4	ENSP00000418645.1	Q0VAK6-1
	LMOD3	ENST00000489031.5	TSL:2	c.*152A>C		3_prime_UTR	Exon 4 of 4	ENSP00000417210.1	Q0VAK6-1

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5435 AN: 152160 Hom.: 302 Cov.: 31

Gnomad AFR AF: 0.0550

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0311

GnomAD4 exome AF: 0.0378 AC: 18341 AN: 485436 Hom.: 1604 Cov.: 7 AF XY: 0.0414 AC XY: 10563 AN XY: 254956

African (AFR) AF: 0.0565 AC: 699 AN: 12370

American (AMR) AF: 0.0182 AC: 317 AN: 17434

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 231 AN: 14650

East Asian (EAS) AF: 0.275 AC: 7885 AN: 28668

South Asian (SAS) AF: 0.128 AC: 5278 AN: 41190

European-Finnish (FIN) AF: 0.00473 AC: 153 AN: 32380

Middle Eastern (MID) AF: 0.0236 AC: 86 AN: 3640

European-Non Finnish (NFE) AF: 0.00930 AC: 2868 AN: 308512

Other (OTH) AF: 0.0310 AC: 824 AN: 26592

GnomAD4 genome AF: 0.0358 AC: 5448 AN: 152280 Hom.: 305 Cov.: 31 AF XY: 0.0395 AC XY: 2944 AN XY: 74452

African (AFR) AF: 0.0552 AC: 2294 AN: 41568

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: 1365 AN: 5158

South Asian (SAS) AF: 0.138 AC: 665 AN: 4816

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0107 AC: 725 AN: 68032

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

Alfa AF: 0.0285 Hom.: 108

Bravo AF: 0.0372

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	-0.64
CADD	Benign	2.3
DANN	Benign	0.87
PhyloP100		-0.23
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: rs1131960; hg19: chr3-69158094; COSMIC: COSV56235583; COSMIC: COSV56235583;