NM_015512.5:c.7151A>G

Variant names:

Variant summary

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

The NM_015512.5(DNAH1):c.7151A>G(p.Asn2384Ser) variant causes a missense change. The variant allele was found at a frequency of 0.109 in 1,612,530 control chromosomes in the GnomAD database, including 10,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. N2384H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.078 ( 616 hom., cov: 32)

Exomes 𝑓: 0.11 ( 10191 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.77

Publications

21 publications found

Variant links:

Genes affected

DNAH1 (HGNC:2940): (dynein axonemal heavy chain 1) This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile. [provided by RefSeq, Feb 2017]

DNAH1 Gene-Disease associations (from GenCC):

spermatogenic failure 18
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
ciliary dyskinesia, primary, 37
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic male infertility due to sperm motility disorder
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DNAH1 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=0.0019221604).

BP6

Variant 3-52375405-A-G is Benign according to our data. Variant chr3-52375405-A-G is described in ClinVar as Benign. ClinVar VariationId is 402602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015512.5. 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
	DNAH1	NM_015512.5	MANE Select	c.7151A>G	p.Asn2384Ser	missense	Exon 45 of 78	NP_056327.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.7151A>G	p.Asn2384Ser	missense	Exon 45 of 78	ENSP00000401514.2
	DNAH1	ENST00000486752.5	TSL:2	n.7412A>G		non_coding_transcript_exon	Exon 45 of 77

Frequencies

GnomAD3 genomes

AF:

0.0779

AC:

11851

AN:

152166

Hom.:

617

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0200

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0742

Gnomad ASJ

AF:

0.126

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0660

Gnomad FIN

AF:

0.0526

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.102

GnomAD2 exomes

AF:

0.0836

AC:

20628

AN:

246688

AF XY:

0.0848

show subpopulations

Gnomad AFR exome

AF:

0.0179

Gnomad AMR exome

AF:

0.0634

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.000279

Gnomad FIN exome

AF:

0.0566

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.0913

GnomAD4 exome

AF:

0.112

AC:

163898

AN:

1460246

Hom.:

10191

Cov.:

AF XY:

0.111

AC XY:

80613

AN XY:

726340

show subpopulations

African (AFR)

AF:

0.0188

AC:

630

AN:

33464

American (AMR)

AF:

0.0663

AC:

2954

AN:

44584

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

3135

AN:

26104

East Asian (EAS)

AF:

0.000328

AC:

AN:

39680

South Asian (SAS)

AF:

0.0751

AC:

6462

AN:

85996

European-Finnish (FIN)

AF:

0.0593

AC:

3143

AN:

52970

Middle Eastern (MID)

AF:

0.0988

AC:

570

AN:

5768

European-Non Finnish (NFE)

AF:

0.127

AC:

140638

AN:

1111350

Other (OTH)

AF:

0.105

AC:

6353

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

7732

15464

23197

30929

38661

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5052

10104

15156

20208

25260

<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:

0.0778

AC:

11847

AN:

152284

Hom.:

616

Cov.:

AF XY:

0.0751

AC XY:

5592

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0200

AC:

830

AN:

41578

American (AMR)

AF:

0.0741

AC:

1133

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.126

AC:

435

AN:

3466

East Asian (EAS)

AF:

0.000772

AC:

AN:

5184

South Asian (SAS)

AF:

0.0667

AC:

322

AN:

4826

European-Finnish (FIN)

AF:

0.0526

AC:

558

AN:

10618

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.121

AC:

8255

AN:

68000

Other (OTH)

AF:

0.101

AC:

213

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

569

1138

1706

2275

2844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.105

Hom.:

2094

Bravo

AF:

0.0763

TwinsUK

AF:

0.130

AC:

483

ALSPAC

AF:

0.127

AC:

491

ESP6500AA

AF:

0.0183

AC:

ESP6500EA

AF:

0.122

AC:

1026

ExAC

AF:

0.0828

AC:

10023

Asia WGS

AF:

0.0260

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.67

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.0

PhyloP100

3.8

PrimateAI

Benign

0.28

PROVEAN

Benign

1.0

REVEL

Benign

0.059

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.052

MPC

0.098

ClinPred

0.0017

GERP RS

2.9

gMVP

0.19

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over