11-103220720-A-G

Variant names:

• chr11-103220720-A-G
• rs137853027
• NM_001080463.2:c.9044A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3015E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:24 U:1
• Conservation: PhyloP100: 9.32
• Publications: 15 publications found

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]

DYNC2H1 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: Splicing predictors support a deleterious 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 VariationId is 6503.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080463.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.9044A>G	p.Asp3015Gly	missense	Exon 57 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.9044A>G	p.Asp3015Gly	missense	Exon 57 of 89	NP_001368.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.9044A>G	p.Asp3015Gly	missense	Exon 57 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.9044A>G	p.Asp3015Gly	missense	Exon 57 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+86301A>G		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152128 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000241 AC: 60 AN: 248578 AF XY: 0.000178

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.000201 AC: 9 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000728 AC: 19 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000276 AC: 307 AN: 1111318

Other (OTH) AF: 0.000232 AC: 14 AN: 60328

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152128 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.000262 AC: 4 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68008

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.000408 Hom.: 2

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:24 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:9

Jun 23, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 30, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 13, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 25, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Asphyxiating thoracic dystrophy 3 Pathogenic:8

May 26, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Oct 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 19, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 02, 2021

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in compound heterozygosity with variant c.10109del

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 19, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jun 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jeune thoracic dystrophy Pathogenic:4

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

May 01, 2018

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

DYNC2H1-related disorder Pathogenic:2

May 07, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jul 02, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Short rib-polydactyly syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137853027; hg19: chr11-103091449;