3-69108814-G-T

Position:

• chr3-69108814-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198271.5(LMOD3):​c.*281C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0547 in 332,896 control chromosomes in the GnomAD database, including 1,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (816 hom., cov: 31)
  • Exomes 𝑓: 0.045 (974 hom.)
• Consequence: LMOD3 NM_198271.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.635

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-69108814-G-T is Benign according to our data. Variant chr3-69108814-G-T is described in ClinVar as [Benign]. Clinvar id is 1234364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.*281C>A		3_prime_UTR_variant	3/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.*281C>A		3_prime_UTR_variant	4/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581	c.*281C>A		3_prime_UTR_variant	3/3	1	NM_198271.5	ENSP00000414670.3
LMOD3	ENST00000475434	c.*281C>A		3_prime_UTR_variant	4/4	5		ENSP00000418645.1
LMOD3	ENST00000489031	c.*281C>A		3_prime_UTR_variant	4/4	2		ENSP00000417210.1

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 10023 AN: 152030 Hom.: 810 Cov.: 31

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0517

GnomAD4 exome AF: 0.0452 AC: 8163 AN: 180746 Hom.: 974 Cov.: 0 AF XY: 0.0438 AC XY: 4045 AN XY: 92438

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.0284

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.332

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.00463

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.0435

GnomAD4 genome AF: 0.0661 AC: 10057 AN: 152150 Hom.: 816 Cov.: 31 AF XY: 0.0693 AC XY: 5154 AN XY: 74368

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.0285

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.00227

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.0512

Alfa AF: 0.0131 Hom.: 17

Bravo AF: 0.0721

Asia WGS AF: 0.186 AC: 647 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.70
DANN	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs1051901; hg19: chr3-69157965;