rs419752

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.11230C>T(p.Arg3744Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0445 in 1,613,794 control chromosomes in the GnomAD database, including 1,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 145 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1630 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.64

Publications

15 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=0.0059680045).

BP6

Variant 3-52395649-C-T is Benign according to our data. Variant chr3-52395649-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478396.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 = 0.038 (5786/152332) while in subpopulation NFE AF = 0.0494 (3363/68024). AF 95% confidence interval is 0.048. There are 145 homozygotes in GnomAd4. There are 2660 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 145 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5 link	c.11230C>T	p.Arg3744Cys	missense_variant	Exon 70 of 78	ENST00000420323.7	NP_056327.4	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006129.2 link	c.11299C>T	p.Arg3767Cys	missense_variant	Exon 72 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.11230C>T	p.Arg3744Cys	missense_variant	Exon 71 of 79		XP_016861619.1	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006131.2 link	c.11173C>T	p.Arg3725Cys	missense_variant	Exon 71 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 link	c.11230C>T	p.Arg3744Cys	missense_variant	Exon 70 of 78	1	NM_015512.5	ENSP00000401514.2		Q9P2D7-4

Frequencies

GnomAD3 genomes

AF:

0.0380

AC:

5785

AN:

152214

Hom.:

144

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0208

Gnomad AMI

AF:

0.0868

Gnomad AMR

AF:

0.0484

Gnomad ASJ

AF:

0.0300

Gnomad EAS

AF:

0.0214

Gnomad SAS

AF:

0.0213

Gnomad FIN

AF:

0.0299

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0494

Gnomad OTH

AF:

0.0439

GnomAD2 exomes

AF:

0.0372

AC:

9249

AN:

248514

AF XY:

0.0375

show subpopulations

Gnomad AFR exome

AF:

0.0220

Gnomad AMR exome

AF:

0.0335

Gnomad ASJ exome

AF:

0.0287

Gnomad EAS exome

AF:

0.0180

Gnomad FIN exome

AF:

0.0323

Gnomad NFE exome

AF:

0.0496

Gnomad OTH exome

AF:

0.0470

GnomAD4 exome

AF:

0.0451

AC:

65969

AN:

1461462

Hom.:

1630

Cov.:

AF XY:

0.0447

AC XY:

32532

AN XY:

727024

show subpopulations

African (AFR)

AF:

0.0230

AC:

770

AN:

33480

American (AMR)

AF:

0.0364

AC:

1629

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

777

AN:

26132

East Asian (EAS)

AF:

0.0166

AC:

659

AN:

39700

South Asian (SAS)

AF:

0.0197

AC:

1702

AN:

86250

European-Finnish (FIN)

AF:

0.0332

AC:

1769

AN:

53230

Middle Eastern (MID)

AF:

0.0362

AC:

209

AN:

5768

European-Non Finnish (NFE)

AF:

0.0501

AC:

55651

AN:

1111826

Other (OTH)

AF:

0.0464

AC:

2803

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

3980

7961

11941

15922

19902

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2038

4076

6114

8152

10190

<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:

0.0380

AC:

5786

AN:

152332

Hom.:

145

Cov.:

AF XY:

0.0357

AC XY:

2660

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0207

AC:

862

AN:

41582

American (AMR)

AF:

0.0484

AC:

740

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

104

AN:

3470

East Asian (EAS)

AF:

0.0210

AC:

109

AN:

5180

South Asian (SAS)

AF:

0.0211

AC:

102

AN:

4830

European-Finnish (FIN)

AF:

0.0299

AC:

318

AN:

10624

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0494

AC:

3363

AN:

68024

Other (OTH)

AF:

0.0458

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

304

608

912

1216

1520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0469

Hom.:

775

Bravo

AF:

0.0395

TwinsUK

AF:

0.0512

AC:

190

ALSPAC

AF:

0.0467

AC:

180

ESP6500AA

AF:

0.0230

AC:

ESP6500EA

AF:

0.0474

AC:

403

ExAC

AF:

0.0366

AC:

4436

Asia WGS

AF:

0.0350

AC:

122

AN:

3478

EpiCase

AF:

0.0501

EpiControl

AF:

0.0540

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

Nov 22, 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) -

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

0.18

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0060

MetaSVM

Benign

-1.2

PhyloP100

4.6

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.4

REVEL

Benign

0.24

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0080

Vest4

0.23

MPC

0.41

ClinPred

0.037

GERP RS

3.2

gMVP

0.68

Mutation Taster

=92/8

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