rs61729402

Variant names:

Variant summary

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

The NM_015512.5(DNAH1):c.1244A>G(p.Lys415Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 1,613,982 control chromosomes in the GnomAD database, including 71 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 66 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.68

Publications

8 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=0.0047029853).

BP6

Variant 3-52332352-A-G is Benign according to our data. Variant chr3-52332352-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0039 (594/152362) while in subpopulation SAS AF = 0.0232 (112/4830). AF 95% confidence interval is 0.0197. There are 5 homozygotes in GnomAd4. There are 302 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5 link	c.1244A>G	p.Lys415Arg	missense_variant	Exon 8 of 78	ENST00000420323.7	NP_056327.4	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006129.2 link	c.1244A>G	p.Lys415Arg	missense_variant	Exon 9 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.1244A>G	p.Lys415Arg	missense_variant	Exon 9 of 79		XP_016861619.1	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006131.2 link	c.1244A>G	p.Lys415Arg	missense_variant	Exon 9 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH1	ENST00000420323.7 link	c.1244A>G	p.Lys415Arg	missense_variant	Exon 8 of 78	1	NM_015512.5	ENSP00000401514.2	Q9P2D7-4
DNAH1	ENST00000486752.5 link	n.1505A>G		non_coding_transcript_exon_variant	Exon 8 of 77	2
DNAH1	ENST00000497875.1 link	n.1409A>G		non_coding_transcript_exon_variant	Exon 9 of 21	2

Frequencies

GnomAD3 genomes

AF:

0.00391

AC:

595

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00904

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00473

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00586

AC:

1456

AN:

248352

AF XY:

0.00687

show subpopulations

Gnomad AFR exome

AF:

0.000842

Gnomad AMR exome

AF:

0.00241

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.00673

Gnomad FIN exome

AF:

0.00158

Gnomad NFE exome

AF:

0.00414

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00586

AC:

8570

AN:

1461620

Hom.:

Cov.:

AF XY:

0.00639

AC XY:

4647

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33480

American (AMR)

AF:

0.00226

AC:

101

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00161

AC:

AN:

26136

East Asian (EAS)

AF:

0.00695

AC:

276

AN:

39700

South Asian (SAS)

AF:

0.0233

AC:

2006

AN:

86256

European-Finnish (FIN)

AF:

0.00150

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00510

AC:

5670

AN:

1111864

Other (OTH)

AF:

0.00568

AC:

343

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

534

1067

1601

2134

2668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

238

476

714

952

1190

<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:

0.00390

AC:

594

AN:

152362

Hom.:

Cov.:

AF XY:

0.00405

AC XY:

302

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41582

American (AMR)

AF:

0.00314

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00906

AC:

AN:

5186

South Asian (SAS)

AF:

0.0232

AC:

112

AN:

4830

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00472

AC:

321

AN:

68032

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00397

Hom.:

Bravo

AF:

0.00311

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000703

AC:

ESP6500EA

AF:

0.00367

AC:

ExAC

AF:

0.00628

AC:

760

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.00403

EpiControl

AF:

0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 09, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.1

PhyloP100

1.7

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.90

REVEL

Benign

0.079

Sift

Benign

0.54

Sift4G

Benign

0.61

Vest4

0.18

MVP

0.25

MPC

0.10

ClinPred

0.015

GERP RS

4.4

gMVP

0.34

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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