rs562263699

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_015512.5(DNAH1):c.10895G>A(p.Arg3632His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,612,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3632C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.96

Publications

1 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: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5 link	c.10895G>A	p.Arg3632His	missense_variant	Exon 68 of 78	ENST00000420323.7	NP_056327.4	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006129.2 link	c.10964G>A	p.Arg3655His	missense_variant	Exon 70 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.10895G>A	p.Arg3632His	missense_variant	Exon 69 of 79		XP_016861619.1	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006131.2 link	c.10838G>A	p.Arg3613His	missense_variant	Exon 69 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 link	c.10895G>A	p.Arg3632His	missense_variant	Exon 68 of 78	1	NM_015512.5	ENSP00000401514.2		Q9P2D7-4

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000894

AC:

AN:

245988

AF XY:

0.0000748

show subpopulations

Gnomad AFR exome

AF:

0.0000665

Gnomad AMR exome

AF:

0.0000585

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000162

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000270

AC:

394

AN:

1460408

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

196

AN XY:

726366

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33466

American (AMR)

AF:

0.0000449

AC:

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85902

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000334

AC:

371

AN:

1111362

Other (OTH)

AF:

0.000166

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000112

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000213

Hom.:

Bravo

AF:

0.000136

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ExAC

AF:

0.0000578

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Oct 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3632 of the DNAH1 protein (p.Arg3632His). This variant is present in population databases (rs562263699, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of primary ciliary dyskinesia (Invitae). ClinVar contains an entry for this variant (Variation ID: 478391). 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. -

Spermatogenic failure 18

Uncertain:1

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.53

PhyloP100

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.90

MVP

0.48

MPC

0.65

ClinPred

0.98

GERP RS

4.5

gMVP

0.89

Mutation Taster

=62/38

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