rs57077886
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong
The NM_170707.4(LMNA):c.29C>T(p.Thr10Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T10P) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
4
8
7
Clinical Significance
Conservation
PhyloP100: 2.80
Genes affected
LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
?
In a region_of_interest Interaction with MLIP (size 129) in uniprot entity LMNA_HUMAN there are 173 pathogenic changes around while only 1 benign (99%) in NM_170707.4
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr1-156114946-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1943785.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
Missense variant where missense usually causes diseases, LMNA
PP5
?
Variant 1-156114947-C-T is Pathogenic according to our data. Variant chr1-156114947-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156114947-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.29C>T | p.Thr10Ile | missense_variant | 1/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.29C>T | p.Thr10Ile | missense_variant | 1/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.29C>T | p.Thr10Ile | missense_variant | 1/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.29C>T | p.Thr10Ile | missense_variant | 1/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1418574Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 701274
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1418574
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
701274
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 27, 2016 | A T10I variant that is likely pathogenic was identified in the LMNA gene. It has been reported in one patient with Seip syndrome (Csoka et al., 2004) and as a de novo variant in one patient with atypical lipodystrophy (Mory et al., 2008). The T10I variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T10I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Functional studies show that a cell line with the T10I likely pathogenic variant from a patient with Seip syndrome had abnormal nuclei (Csoka et al., 2004). Garg et al. (2009) observed nuclear abnormalities in cells from patients with atypical Progeria syndrome who carried the T10I variant - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 15, 2016 | - - |
Lipodystrophy Pathogenic:1
Pathogenic, no assertion criteria provided | research | Medical Research Institute, Tokyo Medical and Dental University | Oct 04, 2017 | Patient, a 31 year-old woman, was noted to present with generalized lipodystrophy in childhood. She had hypertriglyceridemia. Metreleptin therapy was started. Aortic stenosis was noted and aortic valve implantation was conducted. This mutation was heterozygous. - |
Dilated cardiomyopathy 1A Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2003 | - - |
Familial partial lipodystrophy, Dunnigan type Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 18, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.;L;L;L
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;D;D;D
Sift4G
Benign
T;T;T;T;T
Polyphen
B;.;P;P;.
Vest4
MutPred
Loss of phosphorylation at T10 (P = 0.0082);Loss of phosphorylation at T10 (P = 0.0082);Loss of phosphorylation at T10 (P = 0.0082);Loss of phosphorylation at T10 (P = 0.0082);Loss of phosphorylation at T10 (P = 0.0082);
MVP
MPC
1.4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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