rs34690489

chr14-102000093-G-Achr14-102000093-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001376.5(DYNC1H1):c.3909G>A(p.Ala1303=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,178 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1303A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (95 hom.)
• Consequence: DYNC1H1 NM_001376.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.50

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 14-102000093-G-A is Benign according to our data. Variant chr14-102000093-G-A is described in ClinVar as [Benign]. Clinvar id is 128936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102000093-G-A is described in Lovd as [Benign]. Variant chr14-102000093-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2150/152292) while in subpopulation AFR AF= 0.0221 (919/41562). AF 95% confidence interval is 0.0209. There are 23 homozygotes in gnomad4. There are 1022 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2150 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC1H1	NM_001376.5	c.3909G>A	p.Ala1303=	synonymous_variant	17/78	ENST00000360184.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.3909G>A	p.Ala1303=	synonymous_variant	17/78	1	NM_001376.5	P1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2150 AN: 152174 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00884 AC: 2224 AN: 251444 Hom.: 18 AF XY: 0.00840 AC XY: 1141 AN XY: 135904

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00967

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00987 AC: 14436 AN: 1461886 Hom.: 95 Cov.: 33 AF XY: 0.00953 AC XY: 6932 AN XY: 727244

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.0202

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0141 AC: 2150 AN: 152292 Hom.: 23 Cov.: 32 AF XY: 0.0137 AC XY: 1022 AN XY: 74468

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.0200

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0120 Hom.: 9

Bravo AF: 0.0162

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0127

EpiControl AF: 0.0119

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Genetic Services Laboratory, University of Chicago	May 08, 2013	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

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	Invitae	Feb 01, 2024	- -

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

Apr 11, 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	4.0
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs34690489; hg19: chr14-102466430;