rs137853035

Variant names:

• chr11-103177640-A-G
• rs137853035
• NM_001080463.2:c.5959A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001377.3(DYNC2H1):​c.5959A>G​(p.Thr1987Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1987M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.06

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]

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a helix (size 14) in uniprot entity DYHC2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001377.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 11-103177640-A-G is Pathogenic according to our data. Variant chr11-103177640-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.5959A>G	p.Thr1987Ala	missense_variant	Exon 38 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.5959A>G	p.Thr1987Ala	missense_variant	Exon 38 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.5959A>G	p.Thr1987Ala	missense_variant	Exon 38 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.5959A>G	p.Thr1987Ala	missense_variant	Exon 38 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:2

Oct 24, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DYNC2H1 p.Thr1987Ala variant (rs137853035; ClinVar Variation ID 6513), has been previously observed in three siblings with an antenatal diagnosis of short rib polydactyly syndrome (SRP) type III (Dagoneau 2009). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 1987 is highly conserved (Alamut v.2.11) and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on the available information, this variant is considered likely pathogenic. References: 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. -

May 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 16, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The T1987A variant in the DYNC2H1 gene has been reported previously in three fetuses diagnosed with short rib polydactyly type III in a single family (Dagoneau et al., 2009). The T1987A variant is not observed in large population cohorts (Lek et al., 2016). The T1987A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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. We interpret T1987A as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.7	M;M;M;M
PhyloP100		9.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.3	D;.;.;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0080	D;.;.;D
Sift4G	Uncertain	0.017	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.94
MutPred		0.80		Loss of ubiquitination at K1985 (P = 0.1154);Loss of ubiquitination at K1985 (P = 0.1154);Loss of ubiquitination at K1985 (P = 0.1154);Loss of ubiquitination at K1985 (P = 0.1154);
MVP		0.71
MPC		0.38
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.44
gMVP		0.64
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

dbSNP: rs137853035; hg19: chr11-103048369;