rs200158571

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_015512.5(DNAH1):c.9646C>G(p.Leu3216Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,552,314 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L3216L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 0.205

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: 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026437432).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00124 (1736/1399972) while in subpopulation MID AF = 0.00211 (12/5692). AF 95% confidence interval is 0.00147. There are 1 homozygotes in GnomAdExome4. There are 838 alleles in the male GnomAdExome4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DNAH1	NM_015512.5 link	c.9646C>G	p.Leu3216Val	missense_variant	Exon 61 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2 link	c.9715C>G	p.Leu3239Val	missense_variant	Exon 63 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.9646C>G	p.Leu3216Val	missense_variant	Exon 62 of 79		XP_016861619.1
DNAH1	XM_017006131.2 link	c.9589C>G	p.Leu3197Val	missense_variant	Exon 62 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 link	c.9646C>G	p.Leu3216Val	missense_variant	Exon 61 of 78	1	NM_015512.5	ENSP00000401514.2

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000666

AC:

106

AN:

159132

AF XY:

0.000608

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000589

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.000890

GnomAD4 exome

AF:

0.00124

AC:

1736

AN:

1399972

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

838

AN XY:

690540

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

31596

American (AMR)

AF:

0.000448

AC:

AN:

35738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25184

East Asian (EAS)

AF:

0.00

AC:

AN:

35748

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79242

European-Finnish (FIN)

AF:

0.0000606

AC:

AN:

49466

Middle Eastern (MID)

AF:

0.00211

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00153

AC:

1652

AN:

1079212

Other (OTH)

AF:

0.000861

AC:

AN:

58094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

108

216

325

433

541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.000748

AC:

114

AN:

152342

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41574

American (AMR)

AF:

0.000719

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00116

Hom.:

Bravo

AF:

0.000876

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000993

AC:

ExAC

AF:

0.000224

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3216 of the DNAH1 protein (p.Leu3216Val). This variant is present in population databases (rs200158571, 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: 478516). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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

Apr 18, 2019

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oligosynaptic infertility;C4539798:Ciliary dyskinesia, primary, 37

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 06-08-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0089

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.0

PhyloP100

0.20

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.15

Sift

Benign

0.092

Sift4G

Benign

0.087

Vest4

0.58

MVP

0.22

MPC

0.49

ClinPred

0.14

GERP RS

1.6

gMVP

0.50

Mutation Taster

=85/15

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