Genetic Variant LMOD1:p.Arg370Gly (chr1-201899905-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_012134.3(LMOD1):c.1108C>G(p.Arg370Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LMOD1
NM_012134.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.83

Publications

1 publications found

Variant links:

Genes affected

LMOD1 (HGNC:6647): (leiomodin 1) The leiomodin 1 protein has a putative membrane-spanning region and 2 types of tandemly repeated blocks. The transcript is expressed in all tissues tested, with the highest levels in thyroid, eye muscle, skeletal muscle, and ovary. Increased expression of leiomodin 1 may be linked to Graves' disease and thyroid-associated ophthalmopathy. [provided by RefSeq, Jul 2008]

LMOD1 Gene-Disease associations (from GenCC):

megacystis-microcolon-intestinal hypoperistalsis syndrome 3
Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
megacystis-microcolon-intestinal hypoperistalsis syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LMOD1 links:

ENSG00000223774 (HGNC:58701):

ENSG00000223774 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012134.3. 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
	LMOD1	NM_012134.3	MANE Select	c.1108C>G	p.Arg370Gly	missense	Exon 2 of 3	NP_036266.2	P29536-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LMOD1	ENST00000367288.5	TSL:1 MANE Select	c.1108C>G	p.Arg370Gly	missense	Exon 2 of 3	ENSP00000356257.4	P29536-1
LMOD1	ENST00000869075.1		c.262-1507C>G		intron	N/A	ENSP00000539134.1
ENSG00000223774	ENST00000414927.5	TSL:3	n.421G>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000142

AC:

AN:

239856

AF XY:

0.000115

show subpopulations

Gnomad AFR exome

AF:

0.000494

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000575

Gnomad FIN exome

AF:

0.000247

Gnomad NFE exome

AF:

0.000156

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000130

AC:

AN:

1456544

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

724398

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33324

American (AMR)

AF:

0.000115

AC:

AN:

43546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.000128

AC:

AN:

39172

South Asian (SAS)

AF:

0.00

AC:

AN:

85994

European-Finnish (FIN)

AF:

0.0000768

AC:

AN:

52050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1110510

Other (OTH)

AF:

0.00

AC:

AN:

60106

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.251

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.000825

AC:

100

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.76

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.2

PhyloP100

9.8

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.65

Sift

Benign

0.27

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.82

MVP

0.87

MPC

1.1

ClinPred

0.082

GERP RS

3.7

Varity_R

0.30

gMVP

0.75

Mutation Taster

=52/48

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over