rs185283741

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001206927.2(DNAH8):c.11468C>T(p.Ala3823Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 1,611,272 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 2 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.83

Publications

3 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07509413).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000608 (887/1459166) while in subpopulation NFE AF = 0.000739 (821/1110808). AF 95% confidence interval is 0.000696. There are 2 homozygotes in GnomAdExome4. There are 395 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2 link	c.11468C>T	p.Ala3823Val	missense_variant	Exon 77 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.11468C>T	p.Ala3823Val	missense_variant	Exon 77 of 93	5	NM_001206927.2	ENSP00000333363.7

Frequencies

GnomAD3 genomes

AF:

0.000316

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000373

AC:

AN:

249318

AF XY:

0.000319

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000614

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000513

Gnomad NFE exome

AF:

0.000495

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000608

AC:

887

AN:

1459166

Hom.:

Cov.:

AF XY:

0.000544

AC XY:

395

AN XY:

725864

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33362

American (AMR)

AF:

0.000540

AC:

AN:

44446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85776

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

53124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000739

AC:

821

AN:

1110808

Other (OTH)

AF:

0.000365

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.000316

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41494

American (AMR)

AF:

0.0000655

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000438

Hom.:

Bravo

AF:

0.000264

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000437

AC:

EpiCase

AF:

0.000437

EpiControl

AF:

0.000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2

Feb 03, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3823 of the DNAH8 protein (p.Ala3823Val). This variant is present in population databases (rs185283741, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. ClinVar contains an entry for this variant (Variation ID: 569635). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DNAH8 protein function with a negative predictive value of 80%. 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. -

not specified

Uncertain:1

May 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.11468C>T (p.A3823V) alteration is located in exon 77 (coding exon 76) of the DNAH8 gene. This alteration results from a C to T substitution at nucleotide position 11468, causing the alanine (A) at amino acid position 3823 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Spermatogenic failure 46

Uncertain:1

Jan 19, 2021

Johns Hopkins Genomics, Johns Hopkins University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This DNAH8 variant (rs185283741) is present in a large population dataset (gnomAD: 102/280708 total alleles; 0.036%; no homozygotes) and has been reported in ClinVar. It has not been reported in the literature, to our knowledge. One bioinformatic tool queried predicts that this substitution would be tolerated, and the alanine residue at this position is poorly evolutionarily conserved across the species assessed. We consider the clinical significance of c.11432C>T to be uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

T;T;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.0086

MetaRNN

Benign

0.075

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

.;.;M

PhyloP100

1.8

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.3

.;N;N

REVEL

Benign

0.097

Sift

Benign

0.15

.;T;T

Polyphen

0.0070

.;.;B

Vest4

0.42

MVP

0.53

MPC

0.17

ClinPred

0.061

GERP RS

6.0

Varity_R

0.16

gMVP

0.27

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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