rs137853027

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001080463.2(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

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

11
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:22U:1

Conservation

PhyloP100: 9.32
Variant links:
Genes affected
DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 11-103220720-A-G is Pathogenic according to our data. Variant chr11-103220720-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6503.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=12}. Variant chr11-103220720-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DYNC2H1NM_001080463.2 linkuse as main transcriptc.9044A>G p.Asp3015Gly missense_variant 57/90 ENST00000650373.2 NP_001073932.1
DYNC2H1NM_001377.3 linkuse as main transcriptc.9044A>G p.Asp3015Gly missense_variant 57/89 ENST00000375735.7 NP_001368.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DYNC2H1ENST00000650373.2 linkuse as main transcriptc.9044A>G p.Asp3015Gly missense_variant 57/90 NM_001080463.2 ENSP00000497174 A1Q8NCM8-2
DYNC2H1ENST00000375735.7 linkuse as main transcriptc.9044A>G p.Asp3015Gly missense_variant 57/891 NM_001377.3 ENSP00000364887 P3Q8NCM8-1
DYNC2H1ENST00000334267.11 linkuse as main transcriptc.2205+86301A>G intron_variant 1 ENSP00000334021 Q8NCM8-3

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
152128
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.000958
GnomAD3 exomes
AF:
0.000241
AC:
60
AN:
248578
Hom.:
0
AF XY:
0.000178
AC XY:
24
AN XY:
134856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000290
Gnomad ASJ exome
AF:
0.000796
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000929
Gnomad NFE exome
AF:
0.000347
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.000243
AC:
355
AN:
1460812
Hom.:
0
Cov.:
31
AF XY:
0.000239
AC XY:
174
AN XY:
726686
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.000728
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000937
Gnomad4 NFE exome
AF:
0.000276
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000243
AC:
37
AN:
152128
Hom.:
0
Cov.:
33
AF XY:
0.000229
AC XY:
17
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000397
Gnomad4 OTH
AF:
0.000958
Alfa
AF:
0.000413
Hom.:
1
Bravo
AF:
0.000246
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000365
AC:
3
ExAC
AF:
0.000257
AC:
31
EpiCase
AF:
0.000439
EpiControl
AF:
0.000179

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:22Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:8
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsMar 13, 2015- -
Pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 23, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 29, 2024In 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) -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsNov 30, 2019- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalJun 25, 2015- -
Asphyxiating thoracic dystrophy 3 Pathogenic:7
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2009- -
Likely pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityMay 19, 2020This 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. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJul 19, 2023- -
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneSep 02, 2021This variant was observed in compound heterozygosity with variant c.10109del -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 26, 2023- -
Pathogenic, criteria provided, single submitterclinical testingGenomic Medicine Lab, University of California San Francisco-- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 09, 2023The 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. -
Jeune thoracic dystrophy Pathogenic:4
Pathogenic, no assertion criteria providedresearchDan Cohn Lab, University Of California Los AngelesJun 01, 2017- -
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Likely pathogenic, criteria provided, single submitterresearchRare Disease Group, Clinical Genetics, Karolinska InstitutetMay 01, 2018- -
DYNC2H1-related disorder Pathogenic:2
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 18, 2024The 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. -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 07, 2018The 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. -
Fetal growth restriction;C0426790:Narrow chest;C1855340:Bowing of the long bones Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJul 02, 2015- -
Short rib-polydactyly syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;D;.;.
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
.;D;.;D
M_CAP
Benign
0.069
D
MetaRNN
Pathogenic
0.75
D;D;D;D
MetaSVM
Uncertain
0.21
D
MutationAssessor
Pathogenic
3.3
M;M;M;M
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-6.4
D;.;.;D
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0080
D;.;.;D
Sift4G
Uncertain
0.014
D;.;.;D
Polyphen
1.0
D;D;D;D
Vest4
0.90
MVP
0.73
MPC
0.43
ClinPred
0.38
T
GERP RS
6.2
Varity_R
0.96
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.90
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.90
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137853027; hg19: chr11-103091449; API