3-52388284-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015512.5(DNAH1):c.9121C>T(p.Arg3041Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,601,154 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3041H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.018 ( 74 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 100 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.99

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: 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=0.010356903).

BP6

Variant 3-52388284-C-T is Benign according to our data. Variant chr3-52388284-C-T is described in ClinVar as Benign. ClinVar VariationId is 478508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

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.9121C>T	p.Arg3041Cys	missense	Exon 57 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.9121C>T	p.Arg3041Cys	missense	Exon 57 of 78	ENSP00000401514.2	Q9P2D7-4
DNAH1	ENST00000486752.5	TSL:2	n.9382C>T		non_coding_transcript_exon	Exon 57 of 77
DNAH1	ENST00000488988.5	TSL:2	n.711C>T		non_coding_transcript_exon	Exon 5 of 25

Frequencies

GnomAD3 genomes

AF:

0.0184

AC:

2794

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0633

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00460

AC:

1038

AN:

225496

AF XY:

0.00370

show subpopulations

Gnomad AFR exome

AF:

0.0682

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000266

Gnomad OTH exome

AF:

0.00176

GnomAD4 exome

AF:

0.00202

AC:

2933

AN:

1448818

Hom.:

100

Cov.:

AF XY:

0.00177

AC XY:

1270

AN XY:

719336

show subpopulations

African (AFR)

AF:

0.0703

AC:

2337

AN:

33260

American (AMR)

AF:

0.00381

AC:

162

AN:

42472

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25882

East Asian (EAS)

AF:

0.00

AC:

AN:

39094

South Asian (SAS)

AF:

0.000107

AC:

AN:

83842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52526

Middle Eastern (MID)

AF:

0.00209

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000135

AC:

149

AN:

1106018

Other (OTH)

AF:

0.00439

AC:

263

AN:

59972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

185

370

555

740

925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0184

AC:

2798

AN:

152336

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1327

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0632

AC:

2628

AN:

41574

American (AMR)

AF:

0.00856

AC:

131

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68028

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

140

280

419

559

699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00672

Hom.:

Bravo

AF:

0.0219

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0529

AC:

223

ESP6500EA

AF:

0.000236

AC:

ExAC

AF:

0.00526

AC:

637

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance: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

0.31

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.45

PhyloP100

3.0

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.0

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Vest4

0.79

MVP

0.64

MPC

0.67

ClinPred

0.041

GERP RS

4.3

gMVP

0.67

Mutation Taster

=77/23

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over