14-102001510-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001376.5(DYNC1H1):c.4396-25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,613,774 control chromosomes in the GnomAD database, including 20,358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4411 hom., cov: 32)

Exomes 𝑓: 0.13 ( 15947 hom. )

Consequence

DYNC1H1
NM_001376.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.28

Publications

8 publications found

Variant links:

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]

DYNC1H1 Gene-Disease associations (from GenCC):

autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
intellectual disability, autosomal dominant 13
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
neuronopathy, distal hereditary motor
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease axonal type 2O
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DYNC1H1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 14-102001510-A-G is Benign according to our data. Variant chr14-102001510-A-G is described in CliVar as Benign. Clinvar id is 674076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102001510-A-G is described in CliVar as Benign. Clinvar id is 674076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102001510-A-G is described in CliVar as Benign. Clinvar id is 674076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102001510-A-G is described in CliVar as Benign. Clinvar id is 674076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102001510-A-G is described in CliVar as Benign. Clinvar id is 674076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102001510-A-G is described in CliVar as Benign. Clinvar id is 674076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102001510-A-G is described in CliVar as Benign. Clinvar id is 674076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102001510-A-G is described in CliVar as Benign. Clinvar id is 674076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102001510-A-G is described in CliVar as Benign. Clinvar id is 674076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102001510-A-G is described in CliVar as Benign. Clinvar id is 674076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5 link	c.4396-25A>G		intron_variant	Intron 20 of 77	ENST00000360184.10	NP_001367.2	Q14204

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10 link	c.4396-25A>G		intron_variant	Intron 20 of 77	1	NM_001376.5	ENSP00000348965.4		Q14204

Frequencies

GnomAD3 genomes

AF:

0.207

AC:

31491

AN:

151914

Hom.:

4399

Cov.:

show subpopulations

Gnomad AFR

AF:

0.390

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.169

Gnomad EAS

AF:

0.274

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.203

GnomAD2 exomes

AF:

0.173

AC:

43525

AN:

251418

AF XY:

0.168

show subpopulations

Gnomad AFR exome

AF:

0.394

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.179

Gnomad EAS exome

AF:

0.288

Gnomad FIN exome

AF:

0.0964

Gnomad NFE exome

AF:

0.114

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.134

AC:

195251

AN:

1461744

Hom.:

15947

Cov.:

AF XY:

0.135

AC XY:

98311

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.399

AC:

13371

AN:

33472

American (AMR)

AF:

0.211

AC:

9423

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

4609

AN:

26136

East Asian (EAS)

AF:

0.274

AC:

10883

AN:

39698

South Asian (SAS)

AF:

0.226

AC:

19478

AN:

86252

European-Finnish (FIN)

AF:

0.102

AC:

5429

AN:

53420

Middle Eastern (MID)

AF:

0.176

AC:

1018

AN:

5768

European-Non Finnish (NFE)

AF:

0.110

AC:

121779

AN:

1111882

Other (OTH)

AF:

0.153

AC:

9261

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

9917

19833

29750

39666

49583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4840

9680

14520

19360

24200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.208

AC:

31554

AN:

152030

Hom.:

4411

Cov.:

AF XY:

0.206

AC XY:

15310

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.390

AC:

16178

AN:

41440

American (AMR)

AF:

0.196

AC:

2988

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

587

AN:

3470

East Asian (EAS)

AF:

0.275

AC:

1423

AN:

5172

South Asian (SAS)

AF:

0.238

AC:

1144

AN:

4808

European-Finnish (FIN)

AF:

0.102

AC:

1078

AN:

10586

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.112

AC:

7633

AN:

67972

Other (OTH)

AF:

0.202

AC:

427

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1136

2272

3407

4543

5679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.153

Hom.:

1059

Bravo

AF:

0.222

Asia WGS

AF:

0.262

AC:

909

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2O

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal dominant 13

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.0070

(source)

DANN

Benign

0.46

PhyloP100

-3.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over