rs201299120

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_015512.5(DNAH1):c.7193G>A(p.Arg2398His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,611,914 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts 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. R2398C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 17 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.01

Publications

4 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 -16 ACMG points.

BP6

Variant 3-52375988-G-A is Benign according to our data. Variant chr3-52375988-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 478488.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 = 0.00236 (360/152244) while in subpopulation NFE AF = 0.0036 (245/68008). AF 95% confidence interval is 0.00323. There are 4 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DNAH1	NM_015512.5 link	c.7193G>A	p.Arg2398His	missense_variant	Exon 46 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2 link	c.7262G>A	p.Arg2421His	missense_variant	Exon 48 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.7193G>A	p.Arg2398His	missense_variant	Exon 47 of 79		XP_016861619.1
DNAH1	XM_017006131.2 link	c.7262G>A	p.Arg2421His	missense_variant	Exon 48 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 link	c.7193G>A	p.Arg2398His	missense_variant	Exon 46 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5 link	n.7454G>A		non_coding_transcript_exon_variant	Exon 46 of 77	2

Frequencies

GnomAD3 genomes

AF:

0.00236

AC:

359

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00360

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00207

AC:

511

AN:

246984

AF XY:

0.00218

show subpopulations

Gnomad AFR exome

AF:

0.000779

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00342

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00390

AC:

5694

AN:

1459670

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

2773

AN XY:

726176

show subpopulations

African (AFR)

AF:

0.000660

AC:

AN:

33328

American (AMR)

AF:

0.00152

AC:

AN:

44032

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26084

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39562

South Asian (SAS)

AF:

0.00147

AC:

126

AN:

85910

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00468

AC:

5196

AN:

1111322

Other (OTH)

AF:

0.00431

AC:

260

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

290

579

869

1158

1448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

208

416

624

832

1040

<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:

0.00236

AC:

360

AN:

152244

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

162

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.000843

AC:

AN:

41526

American (AMR)

AF:

0.00196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00360

AC:

245

AN:

68008

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

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:

0.00299

Hom.:

Bravo

AF:

0.00255

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000507

AC:

ESP6500EA

AF:

0.00410

AC:

ExAC

AF:

0.00183

AC:

221

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00416

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNAH1: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 06, 2023

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 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.58

M_CAP

Benign

0.0061

MetaRNN

Benign

0.0056

MetaSVM

Benign

-1.0

PhyloP100

3.0

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.72

REVEL

Benign

0.054

Sift

Benign

0.098

Sift4G

Benign

0.066

Vest4

0.37

MVP

0.24

MPC

0.16

ClinPred

0.021

GERP RS

4.5

gMVP

0.31

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.25

Position offset: 1

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