chr6-33772704-G-A
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate
The NM_181336.4(LEMD2):c.1436C>T(p.Ser479Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 34)
Consequence
LEMD2
NM_181336.4 missense
NM_181336.4 missense
Scores
4
9
5
Clinical Significance
Conservation
PhyloP100: 6.87
Genes affected
LEMD2 (HGNC:21244): (LEM domain nuclear envelope protein 2) This gene encodes a LEM domain-containing transmembrane protein of the inner nuclear membrane. The protein is involved in nuclear structure organization and plays a role in cell signaling and differentiation. Mutations in this gene result in Cataract 46, juvenile-onset. Multiple transcript variants have been found for this gene. [provided by RefSeq, Feb 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-33772704-G-A is Pathogenic according to our data. Variant chr6-33772704-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 917488.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-33772704-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LEMD2 | NM_181336.4 | c.1436C>T | p.Ser479Phe | missense_variant | 9/9 | ENST00000293760.10 | |
LEMD2 | NM_001348710.2 | c.1037C>T | p.Ser346Phe | missense_variant | 9/9 | ||
LEMD2 | NM_001143944.1 | c.530C>T | p.Ser177Phe | missense_variant | 8/8 | ||
LEMD2 | NM_001348709.2 | c.530C>T | p.Ser177Phe | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LEMD2 | ENST00000293760.10 | c.1436C>T | p.Ser479Phe | missense_variant | 9/9 | 1 | NM_181336.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Marbach-Rustad progeroid syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 12, 2021 | - - |
Proptosis;C0025990:Micrognathia;C0026034:Narrow mouth;C0040433:Dental crowding;C0040457:Teeth, supernumerary;C0349588:Short stature;C0423757:Thin skin;C0426799:Short clavicles;C0456070:Growth delay;C0549397:Deviated nasal septum;C1280433:Lipoatrophy;C1835884:Triangular face;C1837785:Prominent superficial veins;C1857710:Progeroid facial appearance;C2674432:Reduced bone mineral density;C4021202:Abnormal nasal dorsum morphology;C4025069:Multiple unerupted teeth;C4551520:Intention tremor;C4551563:Microcephaly Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | Mar 21, 2019 | Two individuals with a hitherto unknown genetic disorder caused by the same de novo mutation in LEMD2 (c.1436C>T;p.Ser479Phe). Despite different ages and ethnic backgrounds, both individualsshare a progeria-like facial phenotype and a distinct combination of physical and neurologic anomalies, such as growth retardation;hypoplastic jaws crowded with multiple supernumerary, yet unerupted, teeth; and cerebellar intention tremor. Immunofluorescence an-alyses of patient fibroblasts revealed mutation-induced disturbance of nuclear architecture, recapitulating previously published data inLEMD2-deficient cell lines, and additional experiments suggested mislocalization of mutant LEMD2 protein within the nuclear lamina.Computational analysis of facial features with two different deep neural networks showed phenotypic proximity to other nuclear en-velopathies. One of the algorithms, when trained to recognize syndromic similarity (rather than specific syndromes) in an unsupervisedapproach, clustered both individuals closely together, providing hypothesis-free hints for a common genetic etiology. PMID 30905398 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D
REVEL
Benign
Sift
Uncertain
D;D;.;D
Sift4G
Uncertain
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
0.49, 0.53, 0.59
MutPred
0.40
.;Loss of disorder (P = 0.0197);Loss of disorder (P = 0.0197);.;
MVP
MPC
1.6
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at