dbSNP rs77540135: DNAH8:p.His3735Arg (chr6-38929596-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001206927.2(DNAH8):c.11204A>G(p.His3735Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,612,762 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3735Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 34 hom., cov: 31)

Exomes 𝑓: 0.0029 ( 55 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.15

Publications

8 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 links:

DNAH8-AS1 (HGNC:40188): (DNAH8 antisense RNA 1)

DNAH8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004572153).

BP6

Variant 6-38929596-A-G is Benign according to our data. Variant chr6-38929596-A-G is described in ClinVar as Benign. ClinVar VariationId is 414385.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0127 (1929/151842) while in subpopulation AFR AF = 0.0366 (1516/41398). AF 95% confidence interval is 0.0351. There are 34 homozygotes in GnomAd4. There are 934 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2 link	c.11204A>G	p.His3735Arg	missense_variant	Exon 75 of 93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11 link	c.11204A>G	p.His3735Arg	missense_variant	Exon 75 of 93	5	NM_001206927.2	ENSP00000333363.7

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1923

AN:

151724

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0366

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000948

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00196

Gnomad OTH

AF:

0.0125

GnomAD2 exomes

AF:

0.00513

AC:

1288

AN:

250886

AF XY:

0.00420

show subpopulations

Gnomad AFR exome

AF:

0.0356

Gnomad AMR exome

AF:

0.00831

Gnomad ASJ exome

AF:

0.0178

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00180

Gnomad OTH exome

AF:

0.00506

GnomAD4 exome

AF:

0.00291

AC:

4245

AN:

1460920

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

1961

AN XY:

726722

show subpopulations

African (AFR)

AF:

0.0393

AC:

1313

AN:

33420

American (AMR)

AF:

0.00821

AC:

367

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0166

AC:

434

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000290

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.0000938

AC:

AN:

53292

Middle Eastern (MID)

AF:

0.0130

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00144

AC:

1600

AN:

1111462

Other (OTH)

AF:

0.00706

AC:

426

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

212

424

636

848

1060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<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:

0.0127

AC:

1929

AN:

151842

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

934

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.0366

AC:

1516

AN:

41398

American (AMR)

AF:

0.0123

AC:

188

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000208

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.0000948

AC:

AN:

10544

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00196

AC:

133

AN:

67932

Other (OTH)

AF:

0.0123

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

172

258

344

430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00511

Hom.:

Bravo

AF:

0.0152

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0370

AC:

163

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00545

AC:

662

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00257

EpiControl

AF:

0.00285

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0066

T;T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.41

T;T;T

MetaRNN

Benign

0.0046

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

.;.;N

PhyloP100

3.2

PrimateAI

Benign

0.45

PROVEAN

Benign

0.84

.;N;N

REVEL

Benign

0.084

Sift

Benign

0.24

.;T;T

Polyphen

0.0

.;.;B

Vest4

0.20

MVP

0.49

MPC

0.15

ClinPred

0.012

GERP RS

5.7

Varity_R

0.050

gMVP

0.41

Mutation Taster

=99/1

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