rs794728598
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_170707.4(LMNA):c.3G>A(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
LMNA
NM_170707.4 start_lost
NM_170707.4 start_lost
Scores
6
8
2
Clinical Significance
Conservation
PhyloP100: 5.89
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 20 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_170707.4 (LMNA) was described as [Likely_pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-156114921-G-A is Pathogenic according to our data. Variant chr1-156114921-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 488705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156114921-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.3G>A | p.Met1? | start_lost | 1/12 | ENST00000368300.9 | NP_733821.1 | |
LMNA | NM_005572.4 | c.3G>A | p.Met1? | start_lost | 1/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.3G>A | p.Met1? | start_lost | 1/12 | 1 | NM_170707.4 | ENSP00000357283 | P1 | |
LMNA | ENST00000677389.1 | c.3G>A | p.Met1? | start_lost | 1/10 | NM_005572.4 | ENSP00000503633 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1398804Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 689832
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1398804
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Cov.:
31
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0
AN XY:
689832
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2023 | This sequence change affects the initiator methionine of the LMNA mRNA. The next in-frame methionine is located at codon 187. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with LMNA-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 488705). This variant disrupts a region of the LMNA protein in which other variant(s) (p.Lys32del, p.Asn39Ser. p.Glu82Lys) have been determined to be pathogenic (PMID: 17377071, 18551513, 20160190, 20980393, 21632249). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations | Nov 30, 2020 | We observed the genetic variant c.3G>A (p.M1I) in a 43-y.o. male proband, diagnosed with left ventricular non-compaction and dilatation of all cardiac chambers. The c.3G>A genetic variant leads to mutation in the initiation codon (PVS1 criteria). Neither population data (PM2 criteria) nor functional studies are available for this variant. Online in silico tools predict the p.M1I to have the deleterious effect (PP3 criteria). Additionally, this variant was previously reported as pathogenic (PP5). Two more nucleotide changes were reported in this codon, all of them leading to methionine-isoleucine amino acid substitution. We classify the c.3G>A genetic variant as pathogenic due to the combination of PVS1, PM2, PP3, and PP5 criteria. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2021 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Alters the initiator methionine codon, and the resultant protein would be described as "p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 488705; ClinVar) - |
Dilated cardiomyopathy 1A Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | KTest Genetics, KTest | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
PROVEAN
Benign
N;N;N;N;N
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
P;.;P;P;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0507);Gain of catalytic residue at M1 (P = 0.0507);Gain of catalytic residue at M1 (P = 0.0507);Gain of catalytic residue at M1 (P = 0.0507);Gain of catalytic residue at M1 (P = 0.0507);
MVP
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