chr11-103220720-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_001377.3(DYNC2H1):c.9044A>G(p.Asp3015Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,612,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001377.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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DYNC2H1 | NM_001080463.2 | c.9044A>G | p.Asp3015Gly | missense_variant | Exon 57 of 90 | ENST00000650373.2 | NP_001073932.1 | |
DYNC2H1 | NM_001377.3 | c.9044A>G | p.Asp3015Gly | missense_variant | Exon 57 of 89 | ENST00000375735.7 | NP_001368.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.9044A>G | p.Asp3015Gly | missense_variant | Exon 57 of 90 | NM_001080463.2 | ENSP00000497174.1 | |||
DYNC2H1 | ENST00000375735.7 | c.9044A>G | p.Asp3015Gly | missense_variant | Exon 57 of 89 | 1 | NM_001377.3 | ENSP00000364887.2 | ||
DYNC2H1 | ENST00000334267.11 | c.2205+86301A>G | intron_variant | Intron 15 of 19 | 1 | ENSP00000334021.7 |
Frequencies
GnomAD3 genomes AF: 0.000243 AC: 37AN: 152128Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000241 AC: 60AN: 248578Hom.: 0 AF XY: 0.000178 AC XY: 24AN XY: 134856
GnomAD4 exome AF: 0.000243 AC: 355AN: 1460812Hom.: 0 Cov.: 31 AF XY: 0.000239 AC XY: 174AN XY: 726686
GnomAD4 genome AF: 0.000243 AC: 37AN: 152128Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17AN XY: 74316
ClinVar
Submissions by phenotype
not provided Pathogenic:8
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In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19442771, 30557390, 28492532, 33249554, 37595579, 34627339, 37236975, 31974414, 31935347, 23456818, 29068549, 23339108, 34426522, 35627109, 33726816, 38224688) -
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Asphyxiating thoracic dystrophy 3 Pathogenic:8
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This variant was observed in compound heterozygosity with variant c.10109del -
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This DYNC2H1 variant (rs137853027) is rare (<0.1%) in a large population dataset (gnomAD: 73/279976 total alleles; 0.026%; no homozygotes). It has been reported previously in patients with Short-rib thoracic dysplasia (SRTD) and has an entry in ClinVar. Three bioinformatic tools queried predict that p.Asp3051Gly would be damaging, and the asparatic acid residue at this position is strongly conserved across all species assessed. Bioinformatic analysis predicts that this variant would not affect normal exon 57 splicing, although this has not been confirmed experimentally to our knowledge. In addition, functional studies using patient fibroblasts containing this variant show abnormal accumulation of transport proteins in the tips of cilia, suggesting a disruption of retrograde intraflagellar transport. We consider this variant to be likely pathogenic. -
The DYNC2H1 c.9044A>G; p.Asp3015Gly variant (rs137853027) has been described in the compound heterozygous state in several individuals affected with asphyxiating thoracic dystrophy (ATD; Baujat 2013, Dagoneau 2009, Schmidts 2013, Zhang 2018). It contains an entry in ClinVar (Variation ID: 6503), and is observed in the general population at an overall frequency of 0.026% (73/279976 alleles) in the Genome Aggregation Database. The aspartic acid at codon 3015 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Functional studies using fibroblasts from patients who harbor this variant demonstrate abnormal accumulation of anterograde transport proteins in the tips of cilia and disrupted intraflagellar transport (Schmidts 2013). Based on available information, this variant is considered pathogenic. 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. Schmidts M et al. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. J Med Genet. 2013 May;50(5):309-23. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. -
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Jeune thoracic dystrophy Pathogenic:4
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 3015 of the DYNC2H1 protein (p.Asp3015Gly). This variant is present in population databases (rs137853027, gnomAD 0.08%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 23339108, 23456818, 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6503). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DYNC2H1 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
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DYNC2H1-related disorder Pathogenic:2
The DYNC2H1 c.9044A>G (p.Asp3015Gly) missense variant has been reported in two studies in which it is found in a compound heterozygous state with a null variant in five individuals diagnosed with asphyxiating thoracic dystrophy (ATD), including two from one family. One of the individuals also carried a large deletion in the DYNC2H1 gene (Dagoneau et al. 2009; Schmidts et al. 2013). The p.Asp3015Gly variant was also found in a heterozygous state in three unaffected family members. The variant has not been reported in the literature in association with short-rib polydactyly syndrome which is also associated with variants in the DYNC2H1 gene. The p.Asp3015Gly variant was present at a frequency of < 0.005 in 1210 control chromosomes and is reported at a frequency of 0.000789 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies in patient fibroblasts demonstrated accumulation of transport proteins in the ciliary tips compared to wild type suggesting disrupted retrograde intraflagellar transport in cilia (Schmidts et al. 2013). Based on the collective evidence, the p.Asp3015Gly variant is classified as pathogenic for DYNC2H1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
The DYNC2H1 c.9044A>G variant is predicted to result in the amino acid substitution p.Asp3015Gly. This variant has been reported in the compound heterozygous state in multiple individuals with asphyxiating thoracic dystrophy (Dagoneau et al. 2009. PubMed ID: 19442771; Baujat et al. 2013. PubMed ID: 23339108; Schmidts et al. 2013. PubMed ID: 23456818; Zhang et al. 2017. PubMed ID: 29068549; Marchuk et al. 2018. PubMed ID: 30557390; Čechová et al. 2019. PubMed ID: 31935347; Vora et al. 2020. PubMed ID: 31974414). In vitro functional studies using patient fibroblasts reveal abnormal accumulation of anterograde transport proteins in the tips of cilia, suggesting a disruption of retrograde intraflagellar transport (Schmidts et al. 2013. PubMed ID: 23456818). This variant is interpreted as likely pathogenic. -
Fetal growth restriction;C0426790:Narrow chest;C1855340:Bowing of the long bones Pathogenic:1
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Short rib-polydactyly syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at