rs149496322
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2
The NM_001376.5(DYNC1H1):c.10522C>A(p.Leu3508Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,614,196 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
Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
DYNC1H1
NM_001376.5 missense
NM_001376.5 missense
Scores
4
9
5
Clinical Significance
Conservation
PhyloP100: 4.84
Genes affected
DYNC1H1 (HGNC:2961): (dynein cytoplasmic 1 heavy chain 1) Dyneins are a group of microtubule-activated ATPases that function as molecular motors. They are divided into two subgroups of axonemal and cytoplasmic dyneins. The cytoplasmic dyneins function in intracellular motility, including retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Molecules of conventional cytoplasmic dynein are comprised of 2 heavy chain polypeptides and a number of intermediate and light chains.This gene encodes a member of the cytoplasmic dynein heavy chain family. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DYNC1H1. . Gene score misZ 10.967 (greater than the threshold 3.09). Trascript score misZ 16.053 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant non-syndromic intellectual disability, neuronopathy, distal hereditary motor, intellectual disability, autosomal dominant 13, autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures, Charcot-Marie-Tooth disease axonal type 2O.
BP4
Computational evidence support a benign effect (MetaRNN=0.31022775).
BP6
Variant 14-102034084-C-A is Benign according to our data. Variant chr14-102034084-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 380403.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, Benign=1}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00019 (29/152366) while in subpopulation AMR AF= 0.000327 (5/15304). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 29 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYNC1H1 | NM_001376.5 | c.10522C>A | p.Leu3508Ile | missense_variant | 55/78 | ENST00000360184.10 | NP_001367.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYNC1H1 | ENST00000360184.10 | c.10522C>A | p.Leu3508Ile | missense_variant | 55/78 | 1 | NM_001376.5 | ENSP00000348965.4 |
Frequencies
GnomAD3 genomes AF: 0.000190 AC: 29AN: 152248Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000179 AC: 45AN: 251378Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135870
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GnomAD4 exome AF: 0.000137 AC: 201AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.000136 AC XY: 99AN XY: 727208
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GnomAD4 genome AF: 0.000190 AC: 29AN: 152366Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15AN XY: 74506
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 12, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 02, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | DYNC1H1: PP2, PP3, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 13, 2018 | - - |
Charcot-Marie-Tooth disease axonal type 2O;C3281202:Intellectual disability, autosomal dominant 13;C5780022:Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Apr 14, 2022 | This variant has been reported in the literature in 1 individual with clinical suspicion of Charcot Marie Tooth disease (Volodarsky 2021 PMID:32376792). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.02% (19/68042) (https://gnomad.broadinstitute.org/variant/14-102034084-C-A?dataset=gnomad_r3)). This variant is present in ClinVar (Variation ID:380403). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Intellectual disability, autosomal dominant 13 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Oct 02, 2019 | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 24, 2017 | This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Charcot-Marie-Tooth disease axonal type 2O Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Uncertain
D;.
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at