rs201420305

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001206927.2(DNAH8):c.3706G>A(p.Asp1236Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000108 in 1,574,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. D1236H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.55

Publications

4 publications found

Variant links:

Genes affected

DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]

DNAH8 Gene-Disease associations (from GenCC):

spermatogenic failure 46
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
spermatogenic failure 5
Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox
primary ciliary dyskinesia
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

DNAH8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10797012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2 link	c.3706G>A	p.Asp1236Asn	missense_variant	Exon 27 of 93	ENST00000327475.11	NP_001193856.1	Q96JB1Q8IU65A0A075B6F3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH8	ENST00000327475.11 link	c.3706G>A	p.Asp1236Asn	missense_variant	Exon 27 of 93	5	NM_001206927.2	ENSP00000333363.7	A0A075B6F3
DNAH8	ENST00000359357.7 link	c.3055G>A	p.Asp1019Asn	missense_variant	Exon 25 of 91	2		ENSP00000352312.3	Q96JB1-1
DNAH8	ENST00000449981.6 link	c.3706G>A	p.Asp1236Asn	missense_variant	Exon 26 of 82	5		ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000326

AC:

AN:

214582

AF XY:

0.0000257

show subpopulations

Gnomad AFR exome

AF:

0.000386

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000773

AC:

AN:

1422446

Hom.:

Cov.:

AF XY:

0.00000708

AC XY:

AN XY:

706546

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

31286

American (AMR)

AF:

0.00

AC:

AN:

33428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23902

East Asian (EAS)

AF:

0.00

AC:

AN:

39132

South Asian (SAS)

AF:

0.00

AC:

AN:

79228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1098858

Other (OTH)

AF:

0.0000513

AC:

AN:

58472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

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:

0.00

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1

Jun 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1236 of the DNAH8 protein (p.Asp1236Asn). This variant is present in population databases (rs201420305, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.019

T;T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.0067

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;.;L

PhyloP100

4.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.4

.;N;N

REVEL

Benign

0.071

Sift

Benign

0.34

.;T;T

Polyphen

0.0

.;.;B

Vest4

0.34

MutPred

0.33

.;.;Gain of MoRF binding (P = 0.0799);

MVP

0.48

MPC

0.12

ClinPred

0.019

GERP RS

3.7

Varity_R

0.049

gMVP

0.38

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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