3-69108840-G-A

Variant names:

• chr3-69108840-G-A
• rs188468021
• NM_198271.5:c.*255C>T

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.*255C>T		3_prime_UTR	Exon 3 of 3	NP_938012.2	Q0VAK6-1
	LMOD3	NM_001304418.3		c.*255C>T		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.*255C>T		3_prime_UTR	Exon 3 of 3	ENSP00000414670.3	Q0VAK6-1
	LMOD3	ENST00000475434.1	TSL:5	c.*255C>T		3_prime_UTR	Exon 4 of 4	ENSP00000418645.1	Q0VAK6-1
	LMOD3	ENST00000489031.5	TSL:2	c.*255C>T		3_prime_UTR	Exon 4 of 4	ENSP00000417210.1	Q0VAK6-1

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

African (AFR) AF: 0.00126 AC: 8 AN: 6348

American (AMR) AF: 0.00239 AC: 16 AN: 6706

Ashkenazi Jewish (ASJ) AF: 0.000494 AC: 4 AN: 8098

East Asian (EAS) AF: 0.00 AC: 0 AN: 18240

South Asian (SAS) AF: 0.00260 AC: 12 AN: 4608

European-Finnish (FIN) AF: 0.0117 AC: 206 AN: 17604

Middle Eastern (MID) AF: 0.00176 AC: 2 AN: 1136

European-Non Finnish (NFE) AF: 0.00597 AC: 839 AN: 140550

Other (OTH) AF: 0.00357 AC: 51 AN: 14292

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

African (AFR) AF: 0.00111 AC: 46 AN: 41532

American (AMR) AF: 0.00451 AC: 69 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00656 AC: 446 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00529 Hom.: 0

Bravo AF: 0.00384

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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	-0.77
CADD	Benign	4.0
DANN	Benign	0.71
PhyloP100		-0.20
Mutation Taster		=100/0	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: rs188468021; hg19: chr3-69157991;