3-69108840-G-A

Position:

• chr3-69108840-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198271.5(LMOD3):​c.*255C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 369,820 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (6 hom.)
• Consequence: LMOD3 NM_198271.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.197

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=-0.77).
• BP6: Variant 3-69108840-G-A is Benign according to our data. Variant chr3-69108840-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1188646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00478 (728/152238) while in subpopulation NFE AF= 0.00656 (446/68020). AF 95% confidence interval is 0.00605. There are 3 homozygotes in gnomad4. There are 360 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.*255C>T		3_prime_UTR_variant	3/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.*255C>T		3_prime_UTR_variant	4/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.*255C>T		3_prime_UTR_variant	3/3	1	NM_198271.5	ENSP00000414670	P1
LMOD3	ENST00000475434.1	c.*255C>T		3_prime_UTR_variant	4/4	5		ENSP00000418645	P1
LMOD3	ENST00000489031.5	c.*255C>T		3_prime_UTR_variant	4/4	2		ENSP00000417210	P1

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 728 AN: 152120 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00656

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00523 AC: 1138 AN: 217582 Hom.: 6 Cov.: 3 AF XY: 0.00504 AC XY: 562 AN XY: 111512

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.000494

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00260

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.00597

Gnomad4 OTH exome AF: 0.00357

GnomAD4 genome AF: 0.00478 AC: 728 AN: 152238 Hom.: 3 Cov.: 32 AF XY: 0.00484 AC XY: 360 AN XY: 74406

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.00656

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00529 Hom.: 0

Bravo AF: 0.00384

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.0
DANN	Benign	0.71

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: rs188468021; hg19: chr3-69157991;