rs76591348

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015512.5(DNAH1):c.1351A>G(p.Lys451Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,614,012 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 6 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 4.50

Publications

5 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010901868).

BP6

Variant 3-52344554-A-G is Benign according to our data. Variant chr3-52344554-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290747.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00117 (1716/1461674) while in subpopulation MID AF = 0.00433 (25/5768). AF 95% confidence interval is 0.00301. There are 6 homozygotes in GnomAdExome4. There are 876 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5 link	c.1351A>G	p.Lys451Glu	missense_variant	Exon 9 of 78	ENST00000420323.7	NP_056327.4	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006129.2 link	c.1351A>G	p.Lys451Glu	missense_variant	Exon 10 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.1351A>G	p.Lys451Glu	missense_variant	Exon 10 of 79		XP_016861619.1	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006131.2 link	c.1351A>G	p.Lys451Glu	missense_variant	Exon 10 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH1	ENST00000420323.7 link	c.1351A>G	p.Lys451Glu	missense_variant	Exon 9 of 78	1	NM_015512.5	ENSP00000401514.2	Q9P2D7-4
DNAH1	ENST00000486752.5 link	n.1612A>G		non_coding_transcript_exon_variant	Exon 9 of 77	2
DNAH1	ENST00000497875.1 link	n.1516A>G		non_coding_transcript_exon_variant	Exon 10 of 21	2

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

160

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000967

AC:

241

AN:

249242

AF XY:

0.000991

show subpopulations

Gnomad AFR exome

AF:

0.000387

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.00447

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00129

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.00117

AC:

1716

AN:

1461674

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

876

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33480

American (AMR)

AF:

0.000425

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

128

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000754

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00433

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00124

AC:

1382

AN:

1111844

Other (OTH)

AF:

0.00124

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

179

268

358

447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00104

AC:

159

AN:

152338

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41584

American (AMR)

AF:

0.000457

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00606

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00160

AC:

109

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00132

Hom.:

Bravo

AF:

0.000963

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000238

AC:

ESP6500EA

AF:

0.00154

AC:

ExAC

AF:

0.00103

AC:

125

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Mar 31, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 20, 2023

Revvity Omics, Revvity

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DNAH1-related disorder

Benign:1

Jan 04, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

M_CAP

Benign

0.0089

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

PhyloP100

4.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.3

REVEL

Benign

0.057

Sift

Benign

0.23

Sift4G

Benign

0.44

Vest4

0.54

MVP

0.35

MPC

0.19

ClinPred

0.016

GERP RS

5.0

gMVP

0.56

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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