chr17-78426518-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173628.4(DNAH17):c.12854G>A(p.Arg4285Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 1,613,546 control chromosomes in the GnomAD database, including 748 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4285W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.021 ( 34 hom., cov: 33)

Exomes 𝑓: 0.029 ( 714 hom. )

Consequence

DNAH17
NM_173628.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.12

Publications

10 publications found

Variant links:

Genes affected

DNAH17 (HGNC:2946): (dynein axonemal heavy chain 17) Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. DNAH17 is a heavy chain associated with axonemal dynein (Milisav and Affara, 1998 [PubMed 9545504]).[supplied by OMIM, Mar 2008]

DNAH17 Gene-Disease associations (from GenCC):

spermatogenic failure 39
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
non-syndromic male infertility due to sperm motility disorder
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DNAH17 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=0.0070189238).

BP6

Variant 17-78426518-C-T is Benign according to our data. Variant chr17-78426518-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 402703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0215 (3270/152326) while in subpopulation NFE AF = 0.032 (2176/68004). AF 95% confidence interval is 0.0309. There are 34 homozygotes in GnomAd4. There are 1528 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173628.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH17	NM_173628.4	MANE Select	c.12854G>A	p.Arg4285Gln	missense	Exon 79 of 81	NP_775899.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAH17	ENST00000389840.7	TSL:5 MANE Select	c.12854G>A	p.Arg4285Gln	missense	Exon 79 of 81	ENSP00000374490.6
DNAH17	ENST00000586052.5	TSL:5	n.6015G>A		non_coding_transcript_exon	Exon 33 of 35
DNAH17	ENST00000586850.1	TSL:3	n.386G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3270

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00567

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0260

Gnomad ASJ

AF:

0.0401

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00599

Gnomad FIN

AF:

0.0211

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0320

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.0235

AC:

5879

AN:

250394

AF XY:

0.0234

show subpopulations

Gnomad AFR exome

AF:

0.00437

Gnomad AMR exome

AF:

0.0202

Gnomad ASJ exome

AF:

0.0358

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0217

Gnomad NFE exome

AF:

0.0346

Gnomad OTH exome

AF:

0.0293

GnomAD4 exome

AF:

0.0285

AC:

41714

AN:

1461220

Hom.:

714

Cov.:

AF XY:

0.0277

AC XY:

20106

AN XY:

726860

show subpopulations

African (AFR)

AF:

0.00484

AC:

162

AN:

33466

American (AMR)

AF:

0.0214

AC:

954

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0362

AC:

946

AN:

26108

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39684

South Asian (SAS)

AF:

0.00664

AC:

572

AN:

86178

European-Finnish (FIN)

AF:

0.0228

AC:

1218

AN:

53352

Middle Eastern (MID)

AF:

0.0208

AC:

120

AN:

5766

European-Non Finnish (NFE)

AF:

0.0325

AC:

36096

AN:

1111638

Other (OTH)

AF:

0.0272

AC:

1643

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

2224

4448

6673

8897

11121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1304

2608

3912

5216

6520

<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:

0.0215

AC:

3270

AN:

152326

Hom.:

Cov.:

AF XY:

0.0205

AC XY:

1528

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00565

AC:

235

AN:

41582

American (AMR)

AF:

0.0259

AC:

397

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0401

AC:

139

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0211

AC:

224

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0320

AC:

2176

AN:

68004

Other (OTH)

AF:

0.0232

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

176

351

527

702

878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0297

Hom.:

272

Bravo

AF:

0.0211

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0322

AC:

124

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0331

AC:

285

ExAC

AF:

0.0244

AC:

2957

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0345

EpiControl

AF:

0.0365

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

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:Likely 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: Axonemal dynein, but frequency is high

DNAH17-related disorder

Benign:1

Jan 24, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0070

MetaSVM

Benign

-1.1

PhyloP100

1.1

PrimateAI

Benign

0.48

REVEL

Benign

0.081

Vest4

0.24

ClinPred

0.029

GERP RS

5.0

Varity_R

0.093

gMVP

0.49

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over