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rs57077886

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP2PP5_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. 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

Scores

4
8
7

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 2.80
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a region_of_interest Interaction with MLIP (size 129) in uniprot entity LMNA_HUMAN there are 172 pathogenic changes around while only 1 benign (99%) in NM_170707.4
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
LMNANM_170707.4 linkuse as main transcriptc.29C>T p.Thr10Ile missense_variant 1/12 ENST00000368300.9
LMNANM_005572.4 linkuse as main transcriptc.29C>T p.Thr10Ile missense_variant 1/10 ENST00000677389.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LMNAENST00000368300.9 linkuse as main transcriptc.29C>T p.Thr10Ile missense_variant 1/121 NM_170707.4 P1P02545-1
LMNAENST00000677389.1 linkuse as main transcriptc.29C>T p.Thr10Ile missense_variant 1/10 NM_005572.4 P02545-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1418574
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
701274
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
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
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJan 27, 2016A 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 -
not provided, no classification providedliterature onlyEpithelial Biology; Institute of Medical Biology, Singapore-- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 15, 2016- -
Lipodystrophy Pathogenic:1
Pathogenic, no assertion criteria providedresearchMedical Research Institute, Tokyo Medical and Dental UniversityOct 04, 2017Patient, 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 providedliterature onlyOMIMAug 01, 2003- -
Familial partial lipodystrophy, Dunnigan type Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 18, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
CardioboostCm
Uncertain
0.45
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
Cadd
Pathogenic
26
Dann
Uncertain
1.0
Eigen
Benign
0.060
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.88
D;D;D;D;D
M_CAP
Pathogenic
0.49
D
MetaRNN
Uncertain
0.62
D;D;D;D;D
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Benign
1.3
L;.;L;L;L
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-1.3
N;N;N;N;N
REVEL
Uncertain
0.54
Sift
Benign
0.056
T;T;D;D;D
Sift4G
Benign
0.19
T;T;T;T;T
Polyphen
0.26
B;.;P;P;.
Vest4
0.74
MutPred
0.28
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
0.99
MPC
1.4
ClinPred
0.85
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.26
gMVP
0.64

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs57077886; hg19: chr1-156084738; API