rs570247132

Positions:

• chr3-69122187-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_198271.5(LMOD3):​c.200A>G​(p.Asn67Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000156 in 1,613,456 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (5 hom.)
• Consequence: LMOD3 NM_198271.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.27

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013642222).
• BP6: Variant 3-69122187-T-C is Benign according to our data. Variant chr3-69122187-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 475314.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000919 (14/152292) while in subpopulation SAS AF= 0.00291 (14/4818). AF 95% confidence interval is 0.00176. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMOD3	NM_198271.5	c.200A>G	p.Asn67Ser	missense_variant	1/3	ENST00000420581.7	NP_938012.2
LMOD3	NM_001304418.3	c.200A>G	p.Asn67Ser	missense_variant	2/4		NP_001291347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMOD3	ENST00000420581.7	c.200A>G	p.Asn67Ser	missense_variant	1/3	1	NM_198271.5	ENSP00000414670	P1
LMOD3	ENST00000475434.1	c.200A>G	p.Asn67Ser	missense_variant	2/4	5		ENSP00000418645	P1
LMOD3	ENST00000489031.5	c.200A>G	p.Asn67Ser	missense_variant	2/4	2		ENSP00000417210	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000299 AC: 74 AN: 247846 Hom.: 0 AF XY: 0.000424 AC XY: 57 AN XY: 134480

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00220

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461164 Hom.: 5 Cov.: 32 AF XY: 0.000224 AC XY: 163 AN XY: 726826

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000844 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000306 AC: 37

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.0021	T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.27	.;.;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	N;N;N
MutationTaster	Benign	0.80	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.66	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.10	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.17
MutPred		0.53		Gain of glycosylation at T63 (P = 0.0724);Gain of glycosylation at T63 (P = 0.0724);Gain of glycosylation at T63 (P = 0.0724);
MVP		0.36
MPC		0.022
ClinPred		0.031	T
GERP RS		5.7
Varity_R		0.22
gMVP		0.052

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: rs570247132; hg19: chr3-69171338;