NM_015512.5:c.569T>C

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.569T>C(p.Ile190Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 1,607,330 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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: 1.19

Publications

7 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: Labcorp Genetics (formerly Invitae), ClinGen
ciliary dyskinesia, primary, 37
Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
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=0.0072398186).

BP6

Variant 3-52326302-T-C is Benign according to our data. Variant chr3-52326302-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478464.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 = 0.00393 (599/152238) while in subpopulation SAS AF = 0.0232 (112/4822). AF 95% confidence interval is 0.0197. There are 5 homozygotes in GnomAd4. There are 303 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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	NM_015512.5	MANE Select	c.569T>C	p.Ile190Thr	missense	Exon 4 of 78	NP_056327.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.569T>C	p.Ile190Thr	missense	Exon 4 of 78	ENSP00000401514.2	Q9P2D7-4
DNAH1	ENST00000486752.5	TSL:2	n.830T>C		non_coding_transcript_exon	Exon 4 of 77
DNAH1	ENST00000497875.1	TSL:2	n.734T>C		non_coding_transcript_exon	Exon 5 of 21

Frequencies

GnomAD3 genomes

AF:

0.00394

AC:

600

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00905

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00479

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00600

AC:

1455

AN:

242462

AF XY:

0.00703

show subpopulations

Gnomad AFR exome

AF:

0.000783

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.00687

Gnomad FIN exome

AF:

0.00163

Gnomad NFE exome

AF:

0.00421

Gnomad OTH exome

AF:

0.00301

GnomAD4 exome

AF:

0.00590

AC:

8580

AN:

1455092

Hom.:

Cov.:

AF XY:

0.00643

AC XY:

4655

AN XY:

724066

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33470

American (AMR)

AF:

0.00226

AC:

101

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00161

AC:

AN:

26112

East Asian (EAS)

AF:

0.00713

AC:

283

AN:

39696

South Asian (SAS)

AF:

0.0233

AC:

2009

AN:

86172

European-Finnish (FIN)

AF:

0.00153

AC:

AN:

47200

Middle Eastern (MID)

AF:

0.00521

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00511

AC:

5676

AN:

1111666

Other (OTH)

AF:

0.00570

AC:

344

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

466

931

1397

1862

2328

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:

0.00393

AC:

599

AN:

152238

Hom.:

Cov.:

AF XY:

0.00407

AC XY:

303

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41550

American (AMR)

AF:

0.00314

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00907

AC:

AN:

5180

South Asian (SAS)

AF:

0.0232

AC:

112

AN:

4822

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00478

AC:

325

AN:

67996

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

117

146

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:

0.00408

Hom.:

Bravo

AF:

0.00315

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000967

AC:

ESP6500EA

AF:

0.00381

AC:

ExAC

AF:

0.00632

AC:

765

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.00403

EpiControl

AF:

0.00510

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.089

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0072

MetaSVM

Benign

-1.0

PhyloP100

1.2

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.063

Sift

Benign

0.059

Sift4G

Uncertain

0.0050

Vest4

0.31

MVP

0.41

MPC

0.16

ClinPred

0.015

GERP RS

2.3

gMVP

0.53

Mutation Taster

=93/7

polymorphism

(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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over