rs1555410941

Variant names:

• chr14-102027712-G-A
• rs1555410941
• NM_001376.5:c.9142G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001376.5(DYNC1H1):​c.9142G>A​(p.Glu3048Lys) 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. 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)
• Consequence: DYNC1H1 NM_001376.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 9.72

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 8 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, 0.865
• PP5: Variant 14-102027712-G-A is Pathogenic according to our data. Variant chr14-102027712-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 497397.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}. Variant chr14-102027712-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5	c.9142G>A	p.Glu3048Lys	missense_variant	Exon 47 of 78	ENST00000360184.10	NP_001367.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.9142G>A	p.Glu3048Lys	missense_variant	Exon 47 of 78	1	NM_001376.5	ENSP00000348965.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 19, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 28554554, 25512093, 25609763, 26100331, 24307404, 24970098, 28602352, 33726816, 37806997) -

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

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3048 of the DYNC1H1 protein (p.Glu3048Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DYNC1H1-related conditions (PMID: 24307404). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 497397). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DYNC1H1 function (PMID: 24307404). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.45		Gain of ubiquitination at E3048 (P = 0.0146);.;
MVP		0.81
MPC		2.8
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.82
gMVP		0.92

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: rs1555410941; hg19: chr14-102494049; COSMIC: COSV64143770; COSMIC: COSV64143770;