rs143443167

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_015512.5(DNAH1):c.10438A>G(p.Ile3480Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,613,274 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0010 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3B:1

Conservation

PhyloP100: 2.62

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.049548).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00101 (153/151756) while in subpopulation NFE AF = 0.00171 (116/67890). AF 95% confidence interval is 0.00146. There are 2 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DNAH1	NM_015512.5 link	c.10438A>G	p.Ile3480Val	missense_variant	Exon 65 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2 link	c.10507A>G	p.Ile3503Val	missense_variant	Exon 67 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.10438A>G	p.Ile3480Val	missense_variant	Exon 66 of 79		XP_016861619.1
DNAH1	XM_017006131.2 link	c.10381A>G	p.Ile3461Val	missense_variant	Exon 66 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DNAH1	ENST00000420323.7 link	c.10438A>G	p.Ile3480Val	missense_variant	Exon 65 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5 link	n.10895A>G		non_coding_transcript_exon_variant	Exon 64 of 77	2
DNAH1	ENST00000488988.5 link	n.2224A>G		non_coding_transcript_exon_variant	Exon 12 of 25	2
DNAH1	ENST00000490713.5 link	n.1138A>G		non_coding_transcript_exon_variant	Exon 8 of 20	5		ENSP00000419071.1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

153

AN:

151642

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000461

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000722

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000626

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000811

AC:

202

AN:

249180

AF XY:

0.000799

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.000493

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000279

Gnomad NFE exome

AF:

0.00141

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00184

AC:

2682

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1288

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33478

American (AMR)

AF:

0.000604

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000243

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000694

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00224

AC:

2492

AN:

1111766

Other (OTH)

AF:

0.00119

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

163

326

490

653

816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00101

AC:

153

AN:

151756

Hom.:

Cov.:

AF XY:

0.000769

AC XY:

AN XY:

74160

show subpopulations

African (AFR)

AF:

0.000460

AC:

AN:

41344

American (AMR)

AF:

0.000721

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.000627

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00171

AC:

116

AN:

67890

Other (OTH)

AF:

0.00

AC:

AN:

2094

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:

0.00151

Hom.:

Bravo

AF:

0.000929

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00178

AC:

ExAC

AF:

0.000793

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00124

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3480 of the DNAH1 protein (p.Ile3480Val). This variant is present in population databases (rs143443167, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DNAH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 478384). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNAH1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Primary ciliary dyskinesia

Uncertain:1

Jan 04, 2018

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

May 05, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DNAH1-related disorder

Benign:1

Mar 23, 2022

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

Benign

0.10

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.026

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.41

PhyloP100

2.6

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.97

REVEL

Benign

0.13

Sift

Uncertain

0.020

Sift4G

Uncertain

0.021

Vest4

0.54

MVP

0.59

MPC

0.36

ClinPred

0.023

GERP RS

4.7

gMVP

0.38

Mutation Taster

=81/19

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

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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