NM_001206927.2:c.382G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001206927.2(DNAH8):c.382G>A(p.Glu128Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,607,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. E128D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3547811).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2 link	c.382G>A	p.Glu128Lys	missense_variant	Exon 2 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.382G>A	p.Glu128Lys	missense_variant	Exon 2 of 93	5	NM_001206927.2	ENSP00000333363.7	A0A075B6F3
DNAH8	ENST00000373278.8 link	c.382G>A	p.Glu128Lys	missense_variant	Exon 2 of 5	1		ENSP00000362375.4	Q8IU65
DNAH8	ENST00000449981.6 link	c.382G>A	p.Glu128Lys	missense_variant	Exon 1 of 82	5		ENSP00000415331.2	H0Y7V4
DNAH8	ENST00000359357.7 link	c.-185G>A		5_prime_UTR_variant	Exon 1 of 91	2		ENSP00000352312.3	Q96JB1-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000168

AC:

AN:

238320

AF XY:

0.00000765

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000604

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000481

AC:

AN:

1455270

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723542

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33234

American (AMR)

AF:

0.0000228

AC:

AN:

43824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25888

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1109882

Other (OTH)

AF:

0.0000166

AC:

AN:

60158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000860

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid with lysine at codon 128 of the DNAH8 protein (p.Glu128Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs763048415, ExAC 0.002%). 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

Pathogenic

0.96

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.025

T;.;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.86

D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

3.2

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.1

.;D;N

REVEL

Benign

0.15

Sift

Uncertain

0.0090

.;D;D

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

1.0

.;D;.

Vest4

0.52

MutPred

0.33

Loss of ubiquitination at K127 (P = 0.0175);Loss of ubiquitination at K127 (P = 0.0175);Loss of ubiquitination at K127 (P = 0.0175);

MVP

0.87

ClinPred

0.96

GERP RS

5.9

PromoterAI

-0.023

Neutral

(source)

gMVP

0.58

Mutation Taster

=280/20

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over