rs41314035
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7
The NM_170707.4(LMNA):c.1551G>A(p.Gln517=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000615 in 1,610,982 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00064 ( 1 hom. )
Consequence
LMNA
NM_170707.4 synonymous
NM_170707.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.04
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 Likely_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
?
Variant 1-156137175-G-A is Benign according to our data. Variant chr1-156137175-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199111.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=18, Benign=4}. Variant chr1-156137175-G-A is described in Lovd as [Benign]. Variant chr1-156137175-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=3.04 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.1551G>A | p.Gln517= | synonymous_variant | 9/12 | ENST00000368300.9 | |
| LMNA | NM_005572.4 | c.1551G>A | p.Gln517= | synonymous_variant | 9/10 | ENST00000677389.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.1551G>A | p.Gln517= | synonymous_variant | 9/12 | 1 | NM_170707.4 | P1 | |
| LMNA | ENST00000677389.1 | c.1551G>A | p.Gln517= | synonymous_variant | 9/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? AF: 0.000401 AC: 61AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000294 AC: 71AN: 241472Hom.: 0 AF XY: 0.000237 AC XY: 31AN XY: 131006
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GnomAD4 exome AF: 0.000637 AC: 929AN: 1458674Hom.: 1 Cov.: 32 AF XY: 0.000591 AC XY: 429AN XY: 725414
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:28
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:8
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 17, 2016 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | LMNA: BP4, BP7 - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 17, 2017 | Variant summary: The LMNA c.1551G>A (p.Gln517Gln) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 31/84000 control chromosomes at a frequency of 0.000369, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic LMNA variant (0.0001042), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 28, 2018 | - - |
not specified Uncertain:1Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 11, 2015 | p.Gln517Gln in exon 9 of LMNA: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 27/45996 European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs41314035). - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Cardiomyopathy Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 07, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 26, 2018 | - - |
Charcot-Marie-Tooth disease Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Emery-Dreifuss muscular dystrophy Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Charcot-Marie-Tooth disease type 2B1 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Congenital muscular dystrophy due to LMNA mutation Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Dilated cardiomyopathy 1A Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Hutchinson-Gilford syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Mandibuloacral dysplasia with type A lipodystrophy Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Charcot-Marie-Tooth disease type 2 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Limb-Girdle Muscular Dystrophy, Recessive Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Lethal tight skin contracture syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Familial partial lipodystrophy, Dunnigan type Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Primary dilated cardiomyopathy Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2016 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Emery-Dreifuss muscular dystrophy 2, autosomal dominant Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at