rs1004903

chr14-102048678-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001376.5(DYNC1H1):c.13372+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,611,846 control chromosomes in the GnomAD database, including 38,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8010 hom., cov: 31)
  • Exomes 𝑓: 0.20 (30617 hom.)
• Consequence: DYNC1H1 NM_001376.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.752

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 14-102048678-G-A is Benign according to our data. Variant chr14-102048678-G-A is described in ClinVar as [Benign]. Clinvar id is 128932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102048678-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC1H1	NM_001376.5	c.13372+9G>A		intron_variant		ENST00000360184.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.13372+9G>A		intron_variant		1	NM_001376.5	P1
	ENST00000553701.1	n.346+1767C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44009 AN: 151978 Hom.: 7977 Cov.: 31

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.296

GnomAD3 exomes AF: 0.223 AC: 55695 AN: 250266 Hom.: 7068 AF XY: 0.216 AC XY: 29271 AN XY: 135320

Gnomad AFR exome AF: 0.524

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.252

Gnomad SAS exome AF: 0.204

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.196 AC: 286269 AN: 1459750 Hom.: 30617 Cov.: 33 AF XY: 0.195 AC XY: 141938 AN XY: 726146

Gnomad4 AFR exome AF: 0.530

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.247

Gnomad4 EAS exome AF: 0.233

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.290 AC: 44089 AN: 152096 Hom.: 8010 Cov.: 31 AF XY: 0.287 AC XY: 21355 AN XY: 74362

Gnomad4 AFR AF: 0.522

Gnomad4 AMR AF: 0.237

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.237

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.294

Alfa AF: 0.231 Hom.: 3247

Bravo AF: 0.303

Asia WGS AF: 0.235 AC: 815 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Charcot-Marie-Tooth disease axonal type 2O Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2017	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. -

Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Autosomal dominant cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Intellectual disability, autosomal dominant 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.3
Dann	Benign	0.75

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: rs1004903; hg19: chr14-102515015; COSMIC: COSV64135230; COSMIC: COSV64135230;