rs13749

Positions:

• chr14-102047890-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001376.5(DYNC1H1):​c.13080T>C​(p.Thr4360=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,613,124 control chromosomes in the GnomAD database, including 38,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (9246 hom., cov: 29)
  • Exomes 𝑓: 0.18 (29237 hom.)
• Consequence: DYNC1H1 NM_001376.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -2.08

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-102047890-T-C is Benign according to our data. Variant chr14-102047890-T-C is described in ClinVar as [Benign]. Clinvar id is 128929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102047890-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC1H1	NM_001376.5	c.13080T>C	p.Thr4360=	synonymous_variant	73/78	ENST00000360184.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.13080T>C	p.Thr4360=	synonymous_variant	73/78	1	NM_001376.5	P1
	ENST00000553701.1	n.346+2555A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44567 AN: 151360 Hom.: 9216 Cov.: 29

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.287

GnomAD3 exomes AF: 0.225 AC: 56385 AN: 251050 Hom.: 7987 AF XY: 0.217 AC XY: 29479 AN XY: 135758

Gnomad AFR exome AF: 0.597

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.288

Gnomad SAS exome AF: 0.254

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.183 AC: 267168 AN: 1461646 Hom.: 29237 Cov.: 33 AF XY: 0.184 AC XY: 133540 AN XY: 727132

Gnomad4 AFR exome AF: 0.616

Gnomad4 AMR exome AF: 0.255

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.270

Gnomad4 SAS exome AF: 0.256

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome AF: 0.295 AC: 44657 AN: 151478 Hom.: 9246 Cov.: 29 AF XY: 0.290 AC XY: 21458 AN XY: 74068

Gnomad4 AFR AF: 0.590

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.275

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.285

Alfa AF: 0.201 Hom.: 6950

Bravo AF: 0.319

Asia WGS AF: 0.281 AC: 975 AN: 3478

EpiCase AF: 0.178

EpiControl AF: 0.178

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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 -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

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

- -

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

Jan 08, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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	-0.81
CADD	Benign	0.016
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs13749; hg19: chr14-102514227; COSMIC: COSV64135226; COSMIC: COSV64135226;