rs61749019

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.8266G>A(p.Val2756Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,611,248 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 65 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.24

Publications

6 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=0.004161179).

BP6

Variant 3-52383975-G-A is Benign according to our data. Variant chr3-52383975-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478499.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 = 0.00377 (574/152302) while in subpopulation SAS AF = 0.0233 (112/4814). AF 95% confidence interval is 0.0198. There are 4 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	NM_015512.5	MANE Select	c.8266G>A	p.Val2756Met	missense	Exon 52 of 78	NP_056327.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.8266G>A	p.Val2756Met	missense	Exon 52 of 78	ENSP00000401514.2
	DNAH1	ENST00000486752.5	TSL:2	n.8527G>A		non_coding_transcript_exon	Exon 52 of 77

Frequencies

GnomAD3 genomes

AF:

0.00378

AC:

575

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00442

Gnomad SAS

AF:

0.0235

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00476

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00572

AC:

1391

AN:

243172

AF XY:

0.00681

show subpopulations

Gnomad AFR exome

AF:

0.000940

Gnomad AMR exome

AF:

0.00251

Gnomad ASJ exome

AF:

0.00152

Gnomad EAS exome

AF:

0.00375

Gnomad FIN exome

AF:

0.00161

Gnomad NFE exome

AF:

0.00421

Gnomad OTH exome

AF:

0.00303

GnomAD4 exome

AF:

0.00578

AC:

8436

AN:

1458946

Hom.:

Cov.:

AF XY:

0.00632

AC XY:

4587

AN XY:

725458

show subpopulations

African (AFR)

AF:

0.000688

AC:

AN:

33412

American (AMR)

AF:

0.00232

AC:

103

AN:

44322

Ashkenazi Jewish (ASJ)

AF:

0.00157

AC:

AN:

26048

East Asian (EAS)

AF:

0.00381

AC:

151

AN:

39628

South Asian (SAS)

AF:

0.0232

AC:

1990

AN:

85656

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

53220

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00511

AC:

5676

AN:

1110616

Other (OTH)

AF:

0.00566

AC:

341

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

448

896

1344

1792

2240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

236

472

708

944

1180

<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:

0.00377

AC:

574

AN:

152302

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

291

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000938

AC:

AN:

41568

American (AMR)

AF:

0.00314

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00443

AC:

AN:

5188

South Asian (SAS)

AF:

0.0233

AC:

112

AN:

4814

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00475

AC:

323

AN:

68020

Other (OTH)

AF:

0.00285

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

126

158

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:

0.00395

Hom.:

Bravo

AF:

0.00293

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000524

AC:

ESP6500EA

AF:

0.00365

AC:

ExAC

AF:

0.00600

AC:

725

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

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

0.11

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.034

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.0

PhyloP100

1.2

PrimateAI

Benign

0.25

PROVEAN

Benign

1.1

REVEL

Benign

0.087

Sift

Benign

0.34

Sift4G

Benign

0.28

Vest4

0.14

MVP

0.17

MPC

0.13

ClinPred

0.0024

GERP RS

4.4

gMVP

0.14

Mutation Taster

=99/1

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over