1-156137237-G-C
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate
The NM_170707.4(LMNA):c.1608+5G>C variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
LMNA
NM_170707.4 splice_region, intron
NM_170707.4 splice_region, intron
Scores
2
Splicing: ADA: 0.9989
2
Clinical Significance
Conservation
PhyloP100: 6.34
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-156137237-G-C is Pathogenic according to our data. Variant chr1-156137237-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 66854.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-156137237-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1608+5G>C | splice_region_variant, intron_variant | Intron 9 of 11 | ENST00000368300.9 | NP_733821.1 | ||
LMNA | NM_005572.4 | c.1608+5G>C | splice_region_variant, intron_variant | Intron 9 of 9 | ENST00000677389.1 | NP_005563.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1608+5G>C | splice_region_variant, intron_variant | Intron 9 of 11 | 1 | NM_170707.4 | ENSP00000357283.4 | |||
LMNA | ENST00000677389.1 | c.1608+5G>C | splice_region_variant, intron_variant | Intron 9 of 9 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 14, 2017 | The c.1608+5G>C intronic pathogenic mutation results from a G to C substitution 5 nucleotides after coding exon 9 in the LMNA gene. This mutation strongly segregated with disease in two families with limb-girdle muscular dystrophy (LGMD1B) or LMNA-related dilated cardiomyopathy (Muchir A et al. Hum. Mol. Genet. 2000;9:1453-9; Hoedemaekers YM et al. Circ Cardiovasc Genet, 2010 Jun;3:232-9). RNA studies indicate that this alteration impacts splicing, causing retention of intron 9 and leading to a frameshift and premature truncation of the LMNA protein (Muchir A et al. Hum. Mol. Genet. 2000;9:1453-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Emery-Dreifuss muscular dystrophy 2, autosomal dominant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 22, 2000 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -34
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at