14-102005051-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001376.5(DYNC1H1):​c.5248G>T​(p.Val1750Leu) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1750M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

DYNC1H1
NM_001376.5 missense

Scores

6
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.93
Variant links:
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the DYNC1H1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 122 curated pathogenic missense variants (we use a threshold of 10). The gene has 287 curated benign missense variants. Gene score misZ: 10.967 (above the threshold of 3.09). Trascript score misZ: 16.053 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DYNC1H1NM_001376.5 linkc.5248G>T p.Val1750Leu missense_variant Exon 26 of 78 ENST00000360184.10 NP_001367.2 Q14204

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DYNC1H1ENST00000360184.10 linkc.5248G>T p.Val1750Leu missense_variant Exon 26 of 78 1 NM_001376.5 ENSP00000348965.4 Q14204

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2O Uncertain:1
Sep 08, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYNC1H1 protein function. This variant has not been reported in the literature in individuals affected with DYNC1H1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1750 of the DYNC1H1 protein (p.Val1750Leu). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Uncertain
0.090
D
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.72
D
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Benign
0.0076
T
MetaRNN
Pathogenic
0.80
D
MetaSVM
Benign
-0.93
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-2.6
D
REVEL
Uncertain
0.31
Sift
Uncertain
0.0030
D
Polyphen
0.94
P
Vest4
0.80
MutPred
0.45
Loss of catalytic residue at V1750 (P = 0.2485);
MVP
0.61
MPC
1.5
ClinPred
0.92
D
GERP RS
5.8
Varity_R
0.77
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-102471388; API