12-65238526-A-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_014319.5(LEMD3):​c.1720A>G​(p.Ile574Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000816 in 1,604,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I574M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

LEMD3
NM_014319.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.432

Publications

2 publications found
Variant links:
Genes affected
LEMD3 (HGNC:28887): (LEM domain containing 3) This locus encodes a LEM domain-containing protein. The encoded protein functions to antagonize transforming growth factor-beta signaling at the inner nuclear membrane. Two transcript variants encoding different isoforms have been found for this gene. Mutations in this gene have been associated with osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.[provided by RefSeq, Nov 2009]
LEMD3 Gene-Disease associations (from GenCC):
  • Buschke-Ollendorff syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
  • isolated osteopoikilosis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • melorheostosis with osteopoikilosis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.02901709).
BS1
Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000847 (123/1452600) while in subpopulation NFE AF = 0.0000716 (79/1103662). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in GnomAdExome4. There are 63 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LEMD3NM_014319.5 linkc.1720A>G p.Ile574Val missense_variant Exon 5 of 13 ENST00000308330.3 NP_055134.2 Q9Y2U8A0A024RBB9
LEMD3NM_001167614.2 linkc.1717A>G p.Ile573Val missense_variant Exon 5 of 13 NP_001161086.1 Q9Y2U8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LEMD3ENST00000308330.3 linkc.1720A>G p.Ile574Val missense_variant Exon 5 of 13 1 NM_014319.5 ENSP00000308369.2 Q9Y2U8

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
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:
0.00
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000956
AC:
24
AN:
251018
AF XY:
0.000103
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000416
Gnomad NFE exome
AF:
0.000115
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000847
AC:
123
AN:
1452600
Hom.:
0
Cov.:
29
AF XY:
0.0000871
AC XY:
63
AN XY:
723298
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33274
American (AMR)
AF:
0.0000447
AC:
2
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26064
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39584
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86094
European-Finnish (FIN)
AF:
0.000750
AC:
40
AN:
53358
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5754
European-Non Finnish (NFE)
AF:
0.0000716
AC:
79
AN:
1103662
Other (OTH)
AF:
0.0000333
AC:
2
AN:
60098
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.459
Heterozygous variant carriers
0
5
10
16
21
26
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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
AF:
0.0000526
AC:
8
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74354
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41446
American (AMR)
AF:
0.00
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.000377
AC:
4
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68022
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.519
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000135
Hom.:
0
Bravo
AF:
0.0000491
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Dermatofibrosis lenticularis disseminata Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1
Nov 09, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 574 of the LEMD3 protein (p.Ile574Val). This variant is present in population databases (rs374107839, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LEMD3-related conditions. ClinVar contains an entry for this variant (Variation ID: 310239). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LEMD3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
4.9
DANN
Benign
0.51
DEOGEN2
Benign
0.19
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-0.91
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.53
T
M_CAP
Benign
0.0027
T
MetaRNN
Benign
0.029
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-0.76
N
PhyloP100
0.43
PrimateAI
Benign
0.28
T
PROVEAN
Benign
0.21
N
REVEL
Benign
0.019
Sift
Benign
0.72
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.12
MVP
0.12
ClinPred
0.0026
T
GERP RS
-1.3
Varity_R
0.018
gMVP
0.22
Mutation Taster
=96/4
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

Publications

Other links and lift over

dbSNP: rs374107839; hg19: chr12-65632306; COSMIC: COSV57653607; COSMIC: COSV57653607; API