rs330150

Variant names:

Variant summary

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

The NM_001347886.2(DNAH3):c.4557C>G(p.Ile1519Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,612,088 control chromosomes in the GnomAD database, including 10,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1519T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1526 hom., cov: 31)

Exomes 𝑓: 0.11 ( 8722 hom. )

Consequence

DNAH3
NM_001347886.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.540

Publications

22 publications found

Variant links:

Genes affected

DNAH3 (HGNC:2949): (dynein axonemal heavy chain 3) This gene belongs to the dynein family, whose members encode large proteins that are constituents of the microtubule-associated motor protein complex. This complex is composed of dynein heavy, intermediate and light chains, which can be axonemal or cytoplasmic. This protein is an axonemal dynein heavy chain. It is involved in producing force for ciliary beating by using energy from ATP hydrolysis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

DNAH3 Gene-Disease associations (from GenCC):

male infertility
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

DNAH3 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 (MetaRNN=0.0018554926).

BP6

Variant 16-21039887-G-C is Benign according to our data. Variant chr16-21039887-G-C is described in ClinVar as Benign. ClinVar VariationId is 402723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH3	NM_001347886.2 link	c.4557C>G	p.Ile1519Met	missense_variant	Exon 33 of 62	ENST00000698260.1	NP_001334815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH3	ENST00000698260.1 link	c.4557C>G	p.Ile1519Met	missense_variant	Exon 33 of 62		NM_001347886.2	ENSP00000513632.1

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20013

AN:

152074

Hom.:

1525

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.0859

Gnomad AMR

AF:

0.101

Gnomad ASJ

AF:

0.136

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.0718

Gnomad FIN

AF:

0.0967

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.120

GnomAD2 exomes

AF:

0.109

AC:

27317

AN:

251120

AF XY:

0.108

show subpopulations

Gnomad AFR exome

AF:

0.207

Gnomad AMR exome

AF:

0.0827

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.151

Gnomad FIN exome

AF:

0.0936

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.115

GnomAD4 exome

AF:

0.106

AC:

154045

AN:

1459896

Hom.:

8722

Cov.:

AF XY:

0.105

AC XY:

76073

AN XY:

726352

show subpopulations

African (AFR)

AF:

0.211

AC:

7058

AN:

33400

American (AMR)

AF:

0.0850

AC:

3796

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

3579

AN:

26120

East Asian (EAS)

AF:

0.160

AC:

6346

AN:

39690

South Asian (SAS)

AF:

0.0779

AC:

6716

AN:

86192

European-Finnish (FIN)

AF:

0.0909

AC:

4854

AN:

53416

Middle Eastern (MID)

AF:

0.135

AC:

776

AN:

5758

European-Non Finnish (NFE)

AF:

0.103

AC:

114164

AN:

1110344

Other (OTH)

AF:

0.112

AC:

6756

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

6145

12290

18434

24579

30724

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4254

8508

12762

17016

21270

<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:

0.132

AC:

20022

AN:

152192

Hom.:

1526

Cov.:

AF XY:

0.130

AC XY:

9700

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.198

AC:

8220

AN:

41494

American (AMR)

AF:

0.101

AC:

1552

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

471

AN:

3472

East Asian (EAS)

AF:

0.148

AC:

763

AN:

5170

South Asian (SAS)

AF:

0.0715

AC:

345

AN:

4826

European-Finnish (FIN)

AF:

0.0967

AC:

1027

AN:

10618

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.107

AC:

7280

AN:

68000

Other (OTH)

AF:

0.119

AC:

251

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

862

1724

2585

3447

4309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

210

420

630

840

1050

<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:

0.113

Hom.:

797

Bravo

AF:

0.137

TwinsUK

AF:

0.0974

AC:

361

ALSPAC

AF:

0.0924

AC:

356

ESP6500AA

AF:

0.199

AC:

875

ESP6500EA

AF:

0.101

AC:

868

ExAC

AF:

0.110

AC:

13323

Asia WGS

AF:

0.122

AC:

423

AN:

3478

EpiCase

AF:

0.108

EpiControl

AF:

0.104

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.9

PhyloP100

0.54

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.33

Sift

Uncertain

0.0030

Vest4

0.76

ClinPred

0.063

GERP RS

2.3

Varity_R

0.85

gMVP

0.64

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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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