NM_001206927.2:c.4908G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001206927.2(DNAH8):c.4908G>T(p.Glu1636Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00663 in 1,613,928 control chromosomes in the GnomAD database, including 75 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 71 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.27

Publications

6 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: ClinGen, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004161775).

BP6

Variant 6-38845636-G-T is Benign according to our data. Variant chr6-38845636-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00497 (757/152254) while in subpopulation SAS AF = 0.0191 (92/4816). AF 95% confidence interval is 0.0159. There are 4 homozygotes in GnomAd4. There are 366 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206927.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	NM_001206927.2	MANE Select	c.4908G>T	p.Glu1636Asp	missense	Exon 36 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.4257G>T	p.Glu1419Asp	missense	Exon 35 of 92	NP_001362.2	Q96JB1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.4908G>T	p.Glu1636Asp	missense	Exon 36 of 93	ENSP00000333363.7	A0A075B6F3
DNAH8	ENST00000359357.7	TSL:2	c.4257G>T	p.Glu1419Asp	missense	Exon 34 of 91	ENSP00000352312.3	Q96JB1-1
DNAH8	ENST00000449981.6	TSL:5	c.4908G>T	p.Glu1636Asp	missense	Exon 35 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes

AF:

0.00499

AC:

759

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00735

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00706

AC:

1770

AN:

250884

AF XY:

0.00825

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00370

Gnomad ASJ exome

AF:

0.00368

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00743

Gnomad OTH exome

AF:

0.00654

GnomAD4 exome

AF:

0.00680

AC:

9939

AN:

1461674

Hom.:

Cov.:

AF XY:

0.00737

AC XY:

5357

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33466

American (AMR)

AF:

0.00362

AC:

162

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00379

AC:

AN:

26128

East Asian (EAS)

AF:

0.000151

AC:

AN:

39672

South Asian (SAS)

AF:

0.0226

AC:

1947

AN:

86252

European-Finnish (FIN)

AF:

0.00124

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.0187

AC:

108

AN:

5768

European-Non Finnish (NFE)

AF:

0.00640

AC:

7112

AN:

1111868

Other (OTH)

AF:

0.00671

AC:

405

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

559

1118

1678

2237

2796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

256

512

768

1024

1280

<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:

0.00497

AC:

757

AN:

152254

Hom.:

Cov.:

AF XY:

0.00492

AC XY:

366

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41550

American (AMR)

AF:

0.00556

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0191

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00735

AC:

500

AN:

68018

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00678

Hom.:

Bravo

AF:

0.00486

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.00748

AC:

908

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.00976

EpiControl

AF:

0.00854

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (1)

Spermatogenic failure 46 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0098

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.0

PhyloP100

-1.3

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.51

REVEL

Benign

0.062

Sift

Benign

0.44

Polyphen

0.30

Vest4

0.18

MutPred

0.44

Loss of helix (P = 0.2271)

MVP

0.54

MPC

0.11

ClinPred

0.0067

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.045

gMVP

0.35

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over