3-52360039-G-A

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.4531G>A(p.Val1511Met) variant causes a missense change. The variant allele was found at a frequency of 0.0253 in 1,613,938 control chromosomes in the GnomAD database, including 619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 41 hom., cov: 33)

Exomes 𝑓: 0.026 ( 578 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.92

Publications

11 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=0.004373938).

BP6

Variant 3-52360039-G-A is Benign according to our data. Variant chr3-52360039-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478449.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 = 0.018 (2738/152372) while in subpopulation NFE AF = 0.0286 (1943/68032). AF 95% confidence interval is 0.0275. There are 41 homozygotes in GnomAd4. There are 1245 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 41 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5 link	c.4531G>A	p.Val1511Met	missense_variant	Exon 27 of 78	ENST00000420323.7	NP_056327.4	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006129.2 link	c.4531G>A	p.Val1511Met	missense_variant	Exon 28 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.4531G>A	p.Val1511Met	missense_variant	Exon 28 of 79		XP_016861619.1	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006131.2 link	c.4531G>A	p.Val1511Met	missense_variant	Exon 28 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 link	c.4531G>A	p.Val1511Met	missense_variant	Exon 27 of 78	1	NM_015512.5	ENSP00000401514.2		Q9P2D7-4
DNAH1	ENST00000486752.5 link	n.4792G>A		non_coding_transcript_exon_variant	Exon 27 of 77	2

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2736

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00598

Gnomad AMI

AF:

0.0648

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.00734

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0286

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.0186

AC:

4632

AN:

248978

AF XY:

0.0190

show subpopulations

Gnomad AFR exome

AF:

0.00523

Gnomad AMR exome

AF:

0.0123

Gnomad ASJ exome

AF:

0.0227

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00942

Gnomad NFE exome

AF:

0.0281

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.0261

AC:

38164

AN:

1461566

Hom.:

578

Cov.:

AF XY:

0.0258

AC XY:

18784

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.00406

AC:

136

AN:

33480

American (AMR)

AF:

0.0124

AC:

556

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

579

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0128

AC:

1103

AN:

86258

European-Finnish (FIN)

AF:

0.00984

AC:

524

AN:

53274

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0305

AC:

33930

AN:

1111858

Other (OTH)

AF:

0.0211

AC:

1274

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

2309

4617

6926

9234

11543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1248

2496

3744

4992

6240

<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:

0.0180

AC:

2738

AN:

152372

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1245

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00596

AC:

248

AN:

41586

American (AMR)

AF:

0.0147

AC:

225

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0118

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00734

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0286

AC:

1943

AN:

68032

Other (OTH)

AF:

0.0213

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

139

278

417

556

695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0244

Hom.:

168

Bravo

AF:

0.0183

TwinsUK

AF:

0.0316

AC:

117

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.00627

AC:

ESP6500EA

AF:

0.0291

AC:

248

ExAC

AF:

0.0188

AC:

2284

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: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

- -

Jul 09, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31213628, 29449551) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNAH1: BP4, BS1, BS2 -

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

Benign:1

Feb 03, 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

0.21

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.37

PhyloP100

4.9

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.21

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Vest4

0.20

MPC

0.53

ClinPred

0.051

GERP RS

4.2

gMVP

0.64

Mutation Taster

=94/6

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