NM_001376.5:c.9020G>A

Variant names:

• chr14-102027516-G-A
• rs797045537
• NM_001376.5:c.9020G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PP2 PP3_Moderate BP6

The NM_001376.5(DYNC1H1):​c.9020G>A​(p.Arg3007Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DYNC1H1 NM_001376.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.70

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest AAA 4 (size 269) in uniprot entity DYHC1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001376.5
• 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, 0.907
• BP6: Variant 14-102027516-G-A is Benign according to our data. Variant chr14-102027516-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210886.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5	c.9020G>A	p.Arg3007Gln	missense_variant	Exon 46 of 78	ENST00000360184.10	NP_001367.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.9020G>A	p.Arg3007Gln	missense_variant	Exon 46 of 78	1	NM_001376.5	ENSP00000348965.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2O Uncertain:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3007 of the DYNC1H1 protein (p.Arg3007Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DYNC1H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 210886). 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 DYNC1H1 protein function with a positive predictive value of 95%. 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. -

not specified Benign:1

Apr 02, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.69
MutPred		0.70		Loss of helix (P = 0.2022);.;
MVP		0.84
MPC		2.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.78
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs797045537; hg19: chr14-102493853;