rs137853026
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong
The NM_001080463.2(DYNC2H1):c.11284A>G(p.Met3762Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,609,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001080463.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.11284A>G | p.Met3762Val | missense_variant | 78/90 | ENST00000650373.2 | |
DYNC2H1 | NM_001377.3 | c.11263A>G | p.Met3755Val | missense_variant | 77/89 | ENST00000375735.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.11284A>G | p.Met3762Val | missense_variant | 78/90 | NM_001080463.2 | A1 | ||
DYNC2H1 | ENST00000375735.7 | c.11263A>G | p.Met3755Val | missense_variant | 77/89 | 1 | NM_001377.3 | P3 | |
DYNC2H1 | ENST00000334267.11 | c.2206-131342A>G | intron_variant | 1 | |||||
DYNC2H1 | ENST00000528670.5 | c.442A>G | p.Met148Val | missense_variant, NMD_transcript_variant | 5/17 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00101 AC: 153AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000337 AC: 83AN: 246608Hom.: 0 AF XY: 0.000261 AC XY: 35AN XY: 133850
GnomAD4 exome AF: 0.000152 AC: 222AN: 1457464Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 107AN XY: 724976
GnomAD4 genome ? AF: 0.00101 AC: 154AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76AN XY: 74430
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 12, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2017 | The M3762V variant has been published in the homozygous state in two children affected with skeletal dysplasia born to consanguineous parents; however, these children were also homozygous for another variant in the DYNC2H1 gene (Dagoneau et al., 2009). The M3762V variant is observed in 35/9648 (0.36%) alleles from individuals of African background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M3762V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Asphyxiating thoracic dystrophy 3 Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.039%). The evidence of pathogenicity is insufficient at this time. This variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, flagged submission | literature only | OMIM | May 01, 2009 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 31, 2019 | The DYNC2H1 c.11284A>G; p.Met3762Val variant (rs137853026) is reported in the literature in the homozygous state in multiple individuals affected with asphyxiating thoracic dystrophy, although some of these individuals also carry other variants in cis (Baujat 2013, Dagoneau 2009, Zhang 2018). This variant is reported] in ClinVar (Variation ID: 6501), and is found in the African population with an allele frequency of 0.32% (78/24098 alleles) in the Genome Aggregation Database. The methionine at codon 3762 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the limited clinical and functional data, the significance of the p.Met3762Val variant is uncertain at this time. References: Baujat G et al. Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families. J Med Genet. 2013 Feb;50(2):91-8. Dagoneau N et al. DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. Am J Hum Genet. 2009 May;84(5):706-11. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. - |
Likely pathogenic, flagged submission | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with short-rib thoracic dysplasia 3 with or without polydactyly (MIM#613091). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (153 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated AAA6 region (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported largely as a VUS, but also as likely pathogenic and pathogenic, and has been observed in homozygous individuals with asphyxiating thoracic dysplasia (ATD) and another variant in cis (p.(Met1991Leu)) (ClinVar, LOVD, PMID: 19442771, PMID: 33875766). However, this variant has also been observed in isolation in four additional homozygous and compound heterozygous individuals with ATD or skeletal dysplasia (PMID: 23339108, Johnson K, and Eason J, (2018), PMID: 29068549 ). One individual also had a variant in the CEP57 gene and a composite phenotype (PMID: 31943948). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated within an extended consanguinous family, however as another variant is present in cis , the evidence is inconclusive (PMID: 19442771). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Jeune thoracic dystrophy Pathogenic:2Benign:1
Pathogenic, flagged submission | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Likely pathogenic, flagged submission | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at