chr6-33772704-G-A

Position:

• chr6-33772704-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: LEMD2 NM_181336.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• 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]

LEMD2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 917488.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr6-33772704-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEMD2	NM_181336.4	c.1436C>T	p.Ser479Phe	missense_variant	9/9	ENST00000293760.10	NP_851853.1
LEMD2	NM_001348710.2	c.1037C>T	p.Ser346Phe	missense_variant	9/9		NP_001335639.1
LEMD2	NM_001143944.1	c.530C>T	p.Ser177Phe	missense_variant	8/8		NP_001137416.1
LEMD2	NM_001348709.2	c.530C>T	p.Ser177Phe	missense_variant	9/9		NP_001335638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEMD2	ENST00000293760.10	c.1436C>T	p.Ser479Phe	missense_variant	9/9	1	NM_181336.4	ENSP00000293760.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

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 -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; De novo variant with confirmed parentage in a patient in the published literature (Marbach et al., 2019), in a gene with autosomal recessive inheritance although autosomal dominant inheritance has also been suggested; This variant is associated with the following publications: (PMID: 30905398) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Benign	0.0099	T
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.0	.;M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D;D;.;D
REVEL	Benign	0.27
Sift	Uncertain	0.0060	D;D;.;D
Sift4G	Uncertain	0.0020	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		0.55
MPC		1.6
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.34
gMVP		0.73

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: rs1767330976; hg19: chr6-33740481;